Adrianne Bendich, PhD, FACN, Series Editor
For other titles published in this series, go to www.springer.com/series/7659
NUTRITION AND METABOLISM
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Christos S. Mantzoros, MD, DSc Division of Endocrinology Diabetes and Metabolism Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA USA
Adrianne Bendich, PhD, FACN GlaxoSmithKline Consumer health(Buy now from http://www.drugswell.com)care Parsippany, NJ USA
ISBN: 978-1-60327-452-4 e-ISBN: 978-1-60327-453-1 DOI: 10.1007/978-1-60327-453-1
Library of Congress Control Number: 2009922619
© Humana Press, a part of Springer Science+Business Media, LLC 2009 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science + Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.
Printed on acid-free paper
To my parents, whose lifelong service to their suffering fellow human beings became a true inspiration and enlightened guidance for my professional and personal life
The Nutrition and health(Buy now from http://www.drugswell.com)TM series of books have, as an overriding mission, to provide health(Buy now from http://www.drugswell.com) professionals with texts that are considered essential because each includes:
The series volumes are developed to provide valuable in-depth information to nutrition health(Buy now from http://www.drugswell.com) professionals and health(Buy now from http://www.drugswell.com) providers interested in practical guidelines. Each editor has the potential to examine a chosen area with a broad perspective, both in subject matter as well as in the choice of chapter authors. The international perspective, especially with regard to public health(Buy now from http://www.drugswell.com) initiatives, is emphasized where appropriate. The editors, whose trainings are both research and practice oriented, have the opportunity to develop a primary objective for their book, deﬁne the scope and focus, and then invite the leading authorities from around the world to be part of their initiative. The authors are encouraged to provide an overview of the ﬁeld, discuss their own research, and relate the research ﬁndings to potential human health(Buy now from http://www.drugswell.com) consequences. Because each book is developed de novo, the chapters are coordinated so that the resulting volume imparts greater knowledge than the sum of the information contained in the individual chapters.
Nutrition and Metabolism: Underlying Mechanisms and Clinical Consequences, edited by Christos S. Mantzoros, MD is a very welcome addition to the Nutrition and health(Buy now from http://www.drugswell.com) Series and fully exempliﬁes the Series’ goals. This volume is especially timely since the obesity epidemic continues to increase around the world and the comorbidities, such as the metabolic syndrome, type II diabetes, hypertension, and hyperlipidemia are seen even in very young children. The editor reminds us that, for most people, their weight remains relatively stable despite wide variations in the types of foods we consume each day, differences in caloric content, and differences in daily physical activity. It is only recently that physicians, scientists, and health(Buy now from http://www.drugswell.com) providers have begun to think about the complexities of excess body weight. This volume contains informative chapters that look at the genetics associated with obesity, the role of the nervous system and the endocrine system, the gastrointestinal tract and of great importance, adipose tissue, as more than a fat storage site. The last decade has seen an explosion of identiﬁ cation
and characterization of the many bioactive molecules that are synthesized and secreted by adipose cells (adipokines). The adipokines and other molecules synthesized in the stomach, intestines, pancreas, and other gastrointestinal organs have been associated with the development of obesity and its comorbidities as well as many, often thought of as unrelated, consequences including insulin resistance, cardiovascular complications, lipid disorders, hypertension, and hormonal imbalances as examples. Thus, the relevance of obesity-related pathophysiology to the clinical setting is of great interest to not only academic researchers, but also health(Buy now from http://www.drugswell.com)care providers. This text is the ﬁ rst to synthesize the knowledge base concerning obesity and its comorbidities including metabolic syndrome, diabetes, hypertension, and hyperlipidemia, and relate these to the mechanisms behind the alterations in metabolism that increase chronic disease risk. This unique volume also contains practice guidelines and tools for obesity management to help the practicing health(Buy now from http://www.drugswell.com) professional as well as those professionals who have an interest in the latest, up-to-date information on obesity treatments and their implications for improving human health(Buy now from http://www.drugswell.com) and reducing obesity-related diseases.
This volume serves the dual purposes of providing current clinical assessment and management guidelines as well as relevant background information on the genetics and pathophysiology associated with the consequences of obesity. The chapters include an historic perspective as well as suggestions for future research opportunities. Dr. Mantzoros is an internationally recognized leader in the ﬁ eld of obesity research as well as clinical outcomes. He and his authors are excellent communicators and he has worked tirelessly to develop a book that is destined to be the benchmark in the ﬁ eld because of its extensive, in-depth chapters covering the most important aspects of the complex interactions between cellular functions, diet and obesity, and its impact on disease states. The editor has chosen 32 of the most well-recognized and respected authors from around the world to contribute the 18 informative chapters in the volume. Hallmarks of all of the chapters include complete deﬁnitions of terms with the abbreviations fully deﬁned for the reader and consistent use of terms between chapters. Key features of this comprehensive volume include the informative key points and keywords that are at the beginning of each chapter, appendices that include detailed tables of major nutrient recommendations for weight reduction in the obese as well as for those with diabetes; detailed descriptions of the Dietary Approaches to Stop Hypertension (DASH) diet protocol; an extensive list of foods and their glycemic index and many other practical guidelines to help in patient management. The volume also contains more than 80 detailed tables and informative ﬁgures, an extensive, detailed index, and more than 2,000 up-to-date references that provide the reader with excellent sources of worthwhile information about the role of diet, exercise, food intake, physiology and pathophysiology of obesity, the metabolic syndrome, types I and II diabetes, and other obesity-related comorbidities.
Dr. Mantzoros has coauthored many of the chapters and he has chosen chapter authors who are internationally distinguished researchers, clinicians, and epidemiologists who provide a comprehensive foundation for understanding the role of weight control in the maintenance of human health(Buy now from http://www.drugswell.com) as well as its role in obesity and related co-morbidities. The book is organized into logical sections that provide the reader with an overview of the complexities of weight control. There is an extensive discussion of the genetics of obesity and the involvement of at least 11 human genes in the control of food intake and metabolism. Genetically linked obesity syndromes are described including Prader–Willi syndrome. This chapter includes new information on the genetics of metabolic syndrome, types I and II diabetes and reviews the ﬁndings that link these diseases genetically. The interaction between the central and peripheral nervous systems, the endocrine system, and molecules synthesized during digestion are discussed in the next chapter that introduces the reader to the concepts of metabolic signals, orosensory stimuli, GI tract peptides and adipokines from fat tissue. Explanations are provided for the role of leptin, insulin, peptide YY, ghrelin, visfatin, cholecystokinin, and many other important modulators in human metabolism. An important chapter is devoted to the description of the central nervous system with detailed explanations of the importance of the hypothalamus and the brain stem. We learn that control of appetite resides in the arcuate nucleus area of the hypothalamus, whereas the paraventricular nucleus is involved with energy homeostasis. This chapter reviews the importance of orexigenic and anorexigenic neuropeptides as well as the effects of thyroid hormones, adrenergic receptors, and thermogenic tissues. The ﬁnal chapter in the section on genetics and pathophysiology looks at insulin resistance and its consequences. The concept of adipose tissue inﬂammation is introduced and there is discussion about body fat distribution including the effects of visceral vs. subcutaneous fat.
Childhood obesity is a major public health(Buy now from http://www.drugswell.com) concern as the percentage of young children that are obese or overweight continues to grow globally. There is an extensive review of the published studies that have attempted to control weight gain in children and adolescents most of which do not use pharmacological agents. Certainly, more research is needed in this area as long-term successful strategies have not been developed and well-accepted guidelines for clinical practice are not currently available. Two chapters review recommendations for diet and physical activity for health(Buy now from http://www.drugswell.com)y adults in one chapter and for the prevention and management of diabetes in the other chapter. These chapters discuss the importance of reducing trans fats, total fat, reﬁned grains, and sugar-sweetened beverages. The authors review the data on the importance of physical activity to help control lipid levels and improve energy balance. The ﬁnal chapter in this section examines the association of obesity and cancer risk. Poor dietary habits account for about 35% of incident cancers and smoking accounts for 30%; obesity accounts for 15%. About 16–20% of cancer deaths in US women and 14% in US men can be attributed to obesity. The chapter includes an analysis of the dietary habits around the globe that can result in a sevenfold difference in the rates of breast and prostate cancers between Western type diets and the rates seen in Japan.
Many nations have developed nutrition recommendations for the general population as well as for those individuals who suffer from the co-morbidities associated with obesity including diabetes and cardiovascular disease. This section of the volume considers the guidance that has been provided, reviews the history of the development of US national dietary guidelines and the most recent Food Guide Pyramid, and follows with a provocative chapter by Drs. Willett and Stampfer that questions the scientiﬁc basis for some of the more general national recommendations given in the Pyramid. Nutrition recommendation for those with cardiovascular disease includes reduction of salt, saturated and trans fats and increases in dietary ﬁber, antioxidants, B vitamins, omega-3 fatty acids, mono-unsaturated fatty acids, calcium, and potassium. Examples of food-based intervention studies that have reduced cardiovascular disease (CVD) risk factors including the prudent diet, DASH diet, Mediterranean diet and the guidelines from the American Heart Association and the European Society of Cardiology are discussed in detail. Details are also provided for the assessment of cardiovascular disease including the biochemical markers currently used to stage the patient. This chapter also discussed the role of dietary supplements in CVD management. In the past 20 years, a new ﬁeld of patient care has emerged called medical nutrition therapy (MNT). MNT has been particularly important in the management of patients with types I and II diabetes. Practice guidelines have been developed for children, adolescents, and adults and have been of value in the control of blood glucose levels as well as glycosylated hemoglobin. Diets are recommended that contain levels of essential micronutrients important to the diabetic. This chapter and the additional information in the related appendices provide practical information for the health(Buy now from http://www.drugswell.com) provider. There is also a separate chapter that describes the Mediterranean diet and the clinical studies, including survey data, case–control and intervention studies that have examined the potential for this diet to reduce obesity and CVD.
The ﬁnal section includes in-depth chapters on the clinical assessment and management of obesity and its co-morbidities. There is a comprehensive chapter on lifestyle and pharmacological treatments for obesity. It is of interest that even today that hypercholesterolemia remains undiagnosed in 50% of the US population and 95% remain undertreated. This chapter explains the effects of hypertension, often seen in the obese, on carotid medial intimal thickness and the clinical studies that have included treatments. A comprehensive review of statin use is also included. Accurate diagnosis tools for obesity and diabetes are provided in the next chapter and also include management tools for gestational diabetes. Another informative chapter describes the use of bariatric surgery and the critical importance of the preoperation evaluation. We are reminded that to date weight loss surgery is the only effective treatment for severe, medically complicated, and refractory obesity. Guidelines for patient inclusion, types of operations, and importantly, postoperation care are provided in detail. The ﬁnal chapter reviews the major co-morbidities associated with obesity and weight loss due to bariatric surgery that have not been included in other chapters. These areas include the increased risk of osteoporosis and fracture following bariatric surgery and the increased risk of gallstones that also occurs after this surgery. On the other hand, there appears to be a signiﬁ cant decrease in mortality as well as a decrease in sleep apnea and osteoarthritis. The literature on the increased risk of certain cancers with obesity is also included. Each of the chapter authors has integrated the newest research ﬁndings so the reader can better understand the complex interactions that can result from excess weight gain as well as loss of excess weight.
Given the growing concern with the increase in adult as well as childhood obesity, it is not surprising to ﬁnd that all chapters in this valuable book are devoted to the clinical aspects of obesity, weight control, diabetes, and other chronic diseases associated with obesity. Moreover, both the cultural aspects of weight gain and the emotional triggers of eating are reviewed. Emphasis is also given to the growing awareness that obesity is associated with a low-grade inﬂammatory state. The editor and authors have integrated the information within these chapters so that the health(Buy now from http://www.drugswell.com)care practitioner can provide guidance to the patient about the potential consequences of chronic obesity. The inclusion of both the earlier chapters on the complexity of human physiology and the chapters that contain clinical discussions helps the reader to have a broader basis of understanding of obesity and the attendant co-morbidities.
In conclusion, Nutrition and Metabolism: Underlying Mechanisms and Clinical Consequences, edited by Christos S. Mantzoros, MD provides health(Buy now from http://www.drugswell.com) professionals in many areas of research and practice with the most up-to-date, well-referenced volume on the importance of maintaining normal weight so that obesity and the obesity-related chronic diseases that can adversely affect human health(Buy now from http://www.drugswell.com) are avoided. This volume will serve the reader as the benchmark in this complex area of interrelationships between body weight, the central nervous system, endocrine organs, the GI tract, the biochemical reactions in fat cells, inﬂammation of adipose tissue, and the functioning of all other organ systems in the human body. Moreover, the interactions between obesity, genetic factors, and the numerous co-morbidities are clearly delineated so that students as well as practitioners can better understand the complexities of these interactions. Dr. Mantzoros is applauded for his efforts to develop the most authoritative resource in the ﬁeld to date and this excellent text is a very welcome addition to the Nutrition and health(Buy now from http://www.drugswell.com) series.
Adrianne Bendich, PhD, FACN Parsippany, NJ
Research on obesity spans a wide range of disciplines, from molecular biology to physiology to epidemiology and translational research to clinical medicine. This book attempts to review comprehensively, for practicing clinicians and scientists alike, our current understanding of how nutrition interacts with the genetic substrate as well as environmental-exogenous factors, including physical activity or the lack thereof, to result in insulin resistance and the metabolic syndrome. Furthermore, the causation, epidemiology, clinical presentation, prevention, and treatment of the most common manifestations of disease states associated with the metabolic syndrome are reviewed. After presenting the Scope of the Problem, the first major part of the book is devoted to Genetics and Pathophysiology, the second part of the book presents the Public health(Buy now from http://www.drugswell.com) Perspective of the most prevalent problems associated with nutrition and the metabolic syndrome, whereas the third major part of the book focuses on Clinical Assessment and Management of the main disease states associated with inappropriate nutrition and the metabolic syndrome. Finally, general information useful for both clinicians and researchers alike is presented in the Appendix.
Covering the entire ﬁeld of nutrition or metabolism would have been a daunting task, far beyond the scope of a single volume book. Thus, Nutrition and Metabolism: Underlying Mechanisms and Clinical Consequences offers only an up-to-date and authoritative review of the major scientiﬁc and clinical aspects of the overlapping areas between nutrition and metabolism. I am indebted to all my colleagues, most of them scientists and distinguished professors at Harvard University, for their valuable contributions. I thank the staff at Humana Press for their hard work in putting together this book in close collaboration with staff in my group, especially Lauren Kuhn and Jess Fargnoli. We also wish to express our gratitude to Dr. Adrianne Bendich, the Series Editor, for her thoughtful suggestions.
I certainly hope that the efforts of all of us will not only provide much needed information to our practicing colleagues but also serve as a stimulus for further research in this scientiﬁc topic of utmost importance for the developed world in the twenty-ﬁ rst century. Our mission will be eventually accomplished if, through higher quality research, superior teaching, and consequently improved health(Buy now from http://www.drugswell.com) services, the quality of our prevention programs as well as the quality of health(Buy now from http://www.drugswell.com) care we provide to our suffering fellow human beings is ultimately enhanced.
Christos S. Mantzoros Boston, MA
|Series Preface ..........................................................................................................||vii|
|Part I||Scope of the Problem|
|1||Nutrition and the Metabolic Syndrome: A Twenty-First-Century Epidemic of Obesity and Eating Disorders ..................................................... Christos S. Mantzoros||3|
|Part II||Genetics and Pathophysiology|
|2||Genes and Gene–Environment Interactions in the Pathogenesis of Obesity and the Metabolic Syndrome ........................................................ Despina Sanoudou, Elizabeth Vafiadaki, and Christos S. Mantzoros||11|
|3||Environmental Inputs, Intake of Nutrients, and Endogenous Molecules Contributing to the Regulation of Energy Homeostasis ................ Theodore Kelesidis, Iosif Kelesidis, and Christos S. Mantzoros||41|
|4||Central Integration of Environmental and Endogenous Signals Important in the Regulation of Food Intake and Energy Expenditure .................................................................................. Iosif Kelesidis, Theodore Kelesidis, and Christos S. Mantzoros||77|
|5||Insulin Resistance in States of Energy Excess: Underlying Pathophysiological Concepts ....................................................... Susann Blüher and Christos S. Mantzoros||107|
|Part III||Public health(Buy now from http://www.drugswell.com) Perspective|
|6||Targeting Childhood Obesity Through Lifestyle Modification ...................... Eirini Bathrellou and Mary Yannakoulia||125|
|7||Diet and Physical Activity in the Prevention of Obesity ................................ Frank B. Hu||135|
8 Diet and Exercise in the Prevention and Management of the Metabolic Syndrome ............................................................................. 149
Mary Yannakoulia, Evaggelia Fappa, Janice Jin Hwang,
9 Diet and Physical Activity in Cancer Prevention ............................................ 161
Part IV Nutrition Recommendations
10 Food Guide Pyramids and the 2005 MyPyramid ............................................ 195
11 Nutrition Recommendations for the General Population: Where Is the Science? ..................................................................................... 209 Walter C. Willett and Meir J. Stampfer
12 Nutrition Recommendations and Interventions for Subjects with Cardiovascular Disease ............................................................ 221 Meropi Kontogianni, Mary Yannakoulia, Lauren Kuhn, Sunali Shah, Kristina Day, and Christos S. Mantzoros
13 Medical Nutrition Therapy in the Treatment of Type 1 and Type 2 Diabetes ............................................................................ 245 Olga Kordonouri, Caroline Apovian, Lauren Kuhn, Thomas Danne, and Christos S. Mantzoros
Part V Clinical Assessment and Management
14 Mediterranean Diet in Disease Prevention: Current Perspectives .................. 263
15 Lifestyle and Pharmacology Approaches for the Treatment of Hypertension and Hyperlipidemia ............................................ 279 Peter Oettgen
16 Diagnosis, Evaluation, and Medical Management of Obesity and Diabetes ...................................................................................... 289 Jean L. Chan and Christos S. Mantzoros
17 Surgical Management of Obesity and Postoperative Care.............................. 329 George L. Blackburn, Torsten Olbers, Benjamin E. Schneider, Vivian M. Sanchez, Aoife Brennan, Christos S. Mantzoros, and Daniel B. Jones
|18 Long-Term Impact of Weight Loss on Obesity and Obesity-Associated Comorbidities ................................................................. 347 Janice Jin Hwang, George Blackburn, and Christos S. Mantzoros|
|Part VI Appendix 19 Methods for Classifying, Diagnosing, and Monitoring Obesity ..................... 371 Christos S. Mantzoros|
|20 Methods for Classifying, Diagnosing, and Monitoring Type II Diabetes ....... 385 Christos S. Mantzoros|
|21 Major Nutrition Recommendations and Interventions for Subjects with Hyperlipidemia, Hypertension, and/or Diabetes ................ 393 Christos S. Mantzoros|
|Part VII Resources|
|Resources ................................................................................................................ 407|
|Index ....................................................................................................................... 415|
Caroline Apovian, MD • Division of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
Eirini Bathrellou, MSc • Department of Nutrition and Dietetics, Harokopio University, Athens, Greece George L. Blackburn, PhD, MD • Division of Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Susann Blüher, MD • Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany and Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
Aoife Brennan, MD • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Jean L. Chan, MD • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Thomas Danne, MD • Diabetes Center for Children and Adolescents, Childrens’ Hospital at the Bult, Hannover, Germany Kristina Day, RD • Division of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Cara B. Ebbeling, PhD • Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA Evaggelia Fappa, MSc • Department of Nutrition and Dietetics, Harokopio University, Athens, Greece
Jessica Fargnoli, BS • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Frank B. Hu, PhD, MD • Department of Nutrition, Harvard School of Publichealth(Buy now from http://www.drugswell.com), Boston, MA, USA
Janice Jin Hwang, MD • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Daniel B. Jones MD, MS • Section of Minimally Invasive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Iosif Kelesidis, MD • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Theodore Kelesidis, MD • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Yoon Kim, MD • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Meropi Kontogianni, MD • Department of Nutrition and Dietetics, Harokopio University, Athens, Greece Olga Kordonouri, MD • Diabetes Center for Children and Adolescents, Childrens’ Hospital at the Bult, Hannover, Germany
Lauren Kuhn, BS • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Christos S. Mantzoros, MD, DSc • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
J. Peter Oettgen, MD • Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Torsten Olbers, MD, PhD • Department of Surgery and Gastro Research, Sahlgrenska University Hospital, Goteborg, Sweden
Deanna Olenczuk, BS • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Vivian M. Sanchez, MD • Section of Minimally Invasive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Despina Sanoudou, PhD • Division of Molecular Biology, Foundation for Biomedical Research of the Academy of Athens, Athens, Greece
Benjamin E. Schneider, MD • Section of Minimally Invasive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Sunali Shah, BS • Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Meir Stampfer, MD • Departments of Nutrition and Epidemiology, Harvard School of Public health(Buy now from http://www.drugswell.com), Boston, MA, USA Elizabeth Vafiadaki, PhD • Division of Molecular Biology, Foundation for Biomedical Research of the Academy of Athens, Athens, Greece Walter Willett, MD • Department of Nutrition, Harvard School of Public health(Buy now from http://www.drugswell.com), Boston, MA, USA Alicja Wolk, DMSc • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Mary Yannakoulia, PhD • Department of Nutrition and Dietetics, Harokopio University, Athens, Greece
Inappropriate nutrition, increased calorie intake, and lack of exercise usually lead to obesity and the metabolic syndrome, which, in turn, are responsible for several chronic diseases that affect every aspect of a person s life. In addition to prevention and medical treatment, education is the single most important tool for their management. Education is also of major importance in raising public health(Buy now from http://www.drugswell.com) awareness since it can hopefully help curb the global epidemic of obesity, diabetes, and other disease states associated with the metabolic syndrome. Following is a list of government agencies and nongovernmental organizations that provide information and resources related to nutrition, obesity, and diabetes.
American Association of Diabetes Educators (AADE)
100 West Monroe, Suite 400 Chicago, IL 60603 Tel: 800-338-3633 or 312-424-2426 Fax: 312-424-2427 Diabetes Educator Access Line: 800-TEAMUP4 (800-832-6874) Email: firstname.lastname@example.org Internet: http://www.diabeteseducator.org
American Diabetes Association (ADA)
1701 North Beauregard Street Alexandria, VA 22311 Tel: 800-DIABETES (800-342-2383) Fax: 703-549-6995 Email: email@example.com Internet: http://www.diabetes.org
American Podiatric Medical Association (APMA)
9312 Old Georgetown Road Bethesda, MD 20814-1621 Foot Care Information Center: 800-FOOT-CARE (800-366-8227) Tel: 301-581-9200 Fax: 301-530-2752 Email: firstname.lastname@example.org Internet: http://www.apma.org
Diabetes Exercise and Sports Association (DESA)
8001 Montcastle Drive Nashville, TN 37221 Tel: 800-898-4322 Fax: 602-433-9331 Email: email@example.com Internet: http://www.diabetes-exercise.org
Joslin Diabetes Center
One Joslin Place Boston, MA 02215 Tel: 800-JOSLIN-1 or 617-732-2400 Internet: http://www.joslin.org
Juvenile Diabetes Research Foundation International (JDRF)
120 Wall Street New York, NY 10005-4001 Tel: 800-533-CURE (2873) Fax: 212-785-9595 Email: firstname.lastname@example.org Internet: http://www.jdf.org
International Diabetic Federation (IDF)
Avenue Emile De Mot 19 – B-1000 Brussels, Belgium Tel: +32-2-538-55-11 Fax: +32-2-538-51-14 Email: email@example.com Internet: http://www.idf.org
Centers for Disease Control and Prevention (CDC)
National Center for Chronic Disease Prevention and health(Buy now from http://www.drugswell.com) Promotion Division of Diabetes Translation
P.O. Box 8728 Silver Spring, MD 20910 Tel: 877-CDC-DIAB (877-232-3422) Fax: 301-562-1050 Email: firstname.lastname@example.org Internet: http://www.cdc.gov/diabetes
Academy for Eating Disorders (AED)
60 Revere Drive, Suite 500 Northbrook, IL 60062 Tel: 847-498-4274 Fax: 847-480-9282 Email: email@example.com Internet: http://www.aedweb.org
American Obesity Association (AOA)
1250 24th Street, NW Suite 300 Washington, DC 20037 Tel: 202-776-7711 Fax: 202-776-7712 Internet: http://www.obesity.org
American Society for Bariatric Surgery (ASBS)
100 SW 75th Street Suite 201 Gainesville, FL 32607 Tel: 352-331-4900 Fax: 352-331-4975 Email: firstname.lastname@example.org Internet: http://www.asbs.org
American Society of Bariatric Physicians (ASBP)
2821 S. Parker Rd., Ste. 625 Aurora, CO 80014 Tel: 303-770-2526 Fax: 303-779-4834 Email: email@example.com Internet: http://www.asbp.org
International Association for the Study of Obesity (IASO)
231 North Gower Street, London NW1 2NS, UK Tel: +44-20-7691-1900 Fax: +44-20-7387-6033 Email: firstname.lastname@example.orgemail@example.com Internet: http://www.iaso.org /http://www.iotf.org
North American Association for the Study of Obesity (NAASO)
8630 Fenton Street, Suite 918 Silver Spring, MD 20910 Tel: 301-563-6526 Fax: 301-563-6595 Internet: http://www.naaso.org
American Society for Nutrition (ASN)
9650 Rockville Pike Suite L-5500 Bethesda, MD 20814 Tel: 301-634-7050 Fax: 301-634-7892 Email: firstname.lastname@example.org Internet: http://www.nutrition.org
United States Department of Agriculture (USDA) Center for Nutrition Policy and Promotion
3101 Park Center Drive Room 1034 Alexandria, VA 22302-1594 Tel: 1-888-7pyramid Email: email@example.com Internet: http://www.mypyramid.gov
Harvard School of Public health(Buy now from http://www.drugswell.com) (HSPH) Department of Nutrition
665 Huntington Avenue Boston, MA 02115 Tel: 617-432-1851 Fax: 617-432-2435 Email: firstname.lastname@example.org Internet: http://www.hsph.harvard.edu/academics/nutr
Avenue Appia 20 1211 Geneva 27 Switzerland Fax: +41-22-791-41-56 Email: email@example.com Internet: http://www.who.int/nutrition
National health(Buy now from http://www.drugswell.com) Information Center
P.O. Box 1133 Washington, DC 20013-1133 Tel: 800-336-4797 Email: firstname.lastname@example.org Internet: http://www.health(Buy now from http://www.drugswell.com)ierus.gov
Aristides Daskalopoulos Foundation (IAD)
10, Ziridi str Maroussi 15123, Greece Tel: +30-211-3494101 Fax: +30-211-3494128 Email: email@example.com Internet: http://www.iad.gr
American Society for Parenteral and Enteral Nutrition (ASPEN)
8630 Fenton Street, Suite 412 Silver Spring, MD 20910 Tel: 800-727-4567 or 301-587-6315 Fax: 301-587-2365 Email: firstname.lastname@example.org Internet: http://www.nutritioncare.org
Dietary Guidelines for Americans
U.S. Department of Agriculture and U.S. Department of health(Buy now from http://www.drugswell.com) and Human Services Internet: http://www.health(Buy now from http://www.drugswell.com).gov/dietaryguidelines
U.S. Food and Drug Administration (FDA)
Office of Consumer Affairs 5600 Fishers Lane Rockville, MD 20857 Tel: 888-INFO-FDA (463-6332) and 888-SAFE FOOD (888-723-3366) (Food Information Line) Fax: 301-443-9767 Internet: http://www.fda.gov
Food and Nutrition Information Center (FNIC)
USDA/ARS/National Agricultural Library 10301 Baltimore Avenue, Room 105 Beltsville, MD 20705-2351 Tel: 301-504-5719; TTY: 301-504-6856 Fax: 301-504-6409 Email: email@example.com Internet: http://www.nal.usda.gov/fnic
U.S. Department of Agriculture (USDA)
1400 Independence Ave., SW Washington, DC 20250 Tel: 800-727-9540 and 202-720-2791 Internet: http://www.usda.gov
U.S. Government’s Food Safety Web Site
American Academy of Pediatrics (AAP)
141 Northwest Point Boulevard Elk Grove Village, IL 60007-1098 Tel: 847-434-4000 or 888-227-1770 Email: firstname.lastname@example.org Internet: http://www.aap.org
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Lack of sufﬁ cient nutrition is the main problem of billions of persons in the underdeveloped world, while excessive caloric intake leading to obesity is becoming more and more prevalent in Western societies of afﬂuence. As a result, obesity, which leads to the metabolic syndrome and is thus closely associated with signiﬁ cant morbidity and mortality from diabetes, cardiovascular diseases, and cancers, to mention a few, is considered the epidemic of our century in Western societies.
Positive energy balance, as reﬂected by increasing BMI, is not a recent phenomenon. BMI has been increasing for many decades, but until the mid or late 1970s, it was rather associated with improved health(Buy now from http://www.drugswell.com) and increased longevity. In the past few decades, however, the risk-to-beneﬁt ratio has been shifting in such a way that the continued increase in body fatness is increasingly being recognized as underlying several chronic disease states. This phenomenon is slowing or even reversing gains made in terms of life expectancy in the past. More than 30% of Americans are currently overweight and another 30% are obese, deﬁned as a body mass index (BMI) between 25.0 and 29.9 kg m −2 and higher than 30.0 kg m−2 respectively. Moreover, if the current trends continue, it is expected that by the year 2020 more than 50% of Americans will be obese, possibly making obesity the “norm” and leanness the “exception.” In children, use of the term overweight is usually preferred, to avoid potential stigmatization, and thus the deﬁ nition of obesity in children is based on exceeding the 95th percentile of BMI-for-age using the 2000 Centers for Disease Control charts.
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_1, © Humana Press, a part of Springer Science + Business Media, LLC 2009
Obesity is currently considered as being responsible for increasing morbidity as well as mortality, i.e., for the deaths of several hundreds of thousands of persons every year in Western societies. This fact makes obesity the second important potentially preventable cause of death after smoking. In addition to leading to illness, obesity can reduce signiﬁcantly functional capacity and can increase disability. Realization of the above has prompted a heightened research interest in the factors inﬂ uencing energy balance, and intensiﬁed research efforts on the links between obesity and its complications. It has also created an increasing demand for the study of new methods to diagnose, prevent, or treat obesity and associated comorbidities.
Negative energy balance, either due to lack of availability of appropriate nutrition leading to starvation in underdeveloped nations, or due to voluntary (dieting for weight loss) or involuntary caloric restriction (anorexia nervosa, exercise-induced or hypothalamic amenorrhea) in developed nations, is also of increasing prevalence. Immune dysfunction as well as certain well-deﬁned neuroendocrine abnormalities leading to important adverse health(Buy now from http://www.drugswell.com) consequences such as osteoporosis and infertility are the end result of energy deprivation. Research efforts to identify missing links between energy deﬁ ciency and these pathophysiological abnormalities have also been intensiﬁ ed over the past several years. In the area of epidemiology of obesity, the good news is that increasing rates of obesity appear to be reaching a plateau either because public health(Buy now from http://www.drugswell.com) campaigns and interventions have started working and/or because almost all people with the genetic potential to develop obesity upon exposure to adverse environmental and dietary factors have already developed obesity. The bad news is that the prevalence of obesity continues to rise around the world and that this rising prevalence of obesity is associated with increasing rates of disability, morbidity, and mortality.
1. CAN WE DISCERN HOPEFUL SIGNS IN THE MIDDLE OF THE CURRENT DIFFICULTIES CREATED BY THESE DISEASE STATES?
Several discoveries over the past 10 years have created opportunities for prevention and/or treatment, including discoveries of new genes, molecules, and regulatory pathways. Central, in my opinion, may prove to be developments in the field encompassed by the question: How does negative energy balance lead to neuroendocrine abnormalities? Recent work, mainly from our laboratory, has demonstrated that levels of an adipocyte-secreted hormone, circulating levels of which reflect the amount of energy stored in fat, i.e. leptin, fall in response to negative energy balance and this fall can lead to the neuroendocrine dysfunction that has traditionally been associated with energy, and thus leptin, deficiency states, such as anorexia nervosa and exercise-induced or hypothalamic amenorrhea. Importantly, exogenous administration of leptin, in replacement doses, can correct these neuroendocrine abnormalities in these leptin deficiency states. These novel advances, discussed in the relevant chapters of this book, open new and exciting avenues for diagnosing and treating these conditions in the future. Whether additional factors may also play a role or modify the effects of leptin administration remains to be seen. It also remains to be seen whether falling leptin levels in response to caloric/energy deprivation in obese persons who diet to lose weight may also be responsible for their neuroendocrine changes, which, in turn, tend to defend the original body weight and to make the obese person regain any weight lost in response to dieting.
The prevalence of obesity has been increasing steadily over the past several years. This has been documented in both genders and in every ethnic group and socioeconomic status in Western societies of affluence. Importantly, the increasing prevalence of obesity is not confined to adults; children and adolescents are becoming increasingly overweight and obese. This phenomenon has resulted in increasing prevalence of type 2 diabetes among adolescents and is expected to shift the age of diagnosis of obesity-associated comorbidities, including cardiovascular diseases and cancers, earlier in life. The potential financial, psychological, and public health(Buy now from http://www.drugswell.com) implications of these changes are enormous, and have not yet been fully appreciated.
Recent evidence indicates that in addition to long-recognized genetic and environmental factors, including nutrition and exercise, social networks are closely associated with and may play an important role in the spread of obesity. What are the links between signiﬁcant interpersonal relationships, human behavior, and the pathogenesis of obesity and its complications? What is their impact on obesity prevention and treatment in societies of afﬂuence, as well as in developing societies? Also, how does inappropriate nutrition lead to obesity and how is obesity linked to morbidity and mortality? A considerable amount of work is currently underway to identify and characterize the environmental, social, genetic, cognitive, sensory, metabolic, hormonal, and neural factors leading to obesity and associated comorbidities. The end result is the signiﬁcant growth of speciﬁ c clusters of knowledge in each one of the above speciﬁ c scientiﬁc areas; over the past 15 years, none is currently emerging, unfortunately, as developed enough to explain a meaningful proportion of the problem and/or to allow meaningful predictions of future developments in the areas of prevention or treatment (see below). This not only underlines the multifactorial pathogenesis of the problem but is also considered by many as the last step before major breakthroughs occur on the basis of this accumulating knowledge. Signiﬁ cant progress is being made in the scientiﬁ c area of hormonal and other factors linking excessive amounts of energy stored in adipose tissue with insulin resistance, the metabolic syndrome, and related complications. All these are outlined in detail in the respective chapters of this book.
3. ENVIRONMENTAL AND EXOGENOUS INFLUENCES AS OPPORTUNITIES FOR PUBLIC health(Buy now from http://www.drugswell.com) INTERVENTIONS
Our current environment is distinctly different from the one our ancestors encountered several centuries or even just a century ago. One would thus argue that obesity may be, in part, the result of several factors set in motion by changes in the environment we live in, including the immediate availability of food at the expense of a lower cost and less physical labor, less physical activity, and possibly potential hormonal and epigenetic effects. Questions related to these notions are not only what the best interventions, including diet and exercise, should be, but also how could one help people adhere to an appropriate intervention program for the long term?
Two commonly attacked environmental factors are food marketing practices and institutionally and technologically driven reductions in physical activity. Yet, many have argued that, despite emerging data from controlled interventional studies, available data supporting the above are largely circumstantial and observational in nature. We all realize, however, that if we are to make pervasive and enduring changes to the prevalence of obesity and associated comorbidities, it is likely that we will need to make pervasive and enduring changes to the ways we live across our entire lifespan and these changes are admittedly difﬁcult to implement.
4. MECHANISMS UNDERLYING THE LINK BETWEEN NUTRITION, METABOLISM, AND DISEASE STATES AS OPPORTUNITIES FOR MEDICAL INTERVENTIONS
Although we realize that obesity is associated with adverse health(Buy now from http://www.drugswell.com) outcomes, we do not fully understand the mechanisms underlying these associations. New genes linked to obesity have been discovered and novel neuroendocrine mechanisms have been proposed. Although scientific developments in basic and translational research over the past decade have greatly advanced our understanding of the mechanisms underlying the development of the metabolic syndrome and associated abnormalities, as discussed in detail herein, much more needs to be done in the not so distant future.
Assuming that weight loss is desirable, can we really achieve it? Behavioral modifications such as diet and exercise, while first-line recommendations, remain ultimately largely ineffective at maintaining long-term weight loss at desirable levels. Despite intensive research efforts in the field, it remains to be fully elucidated which diet or dietary pattern, if any, is the most beneficial in terms of reducing weight loss or improving metabolic profile. This is related, in part, to the difficulty in reproducing in an experimental setting the real life dietary patterns of populations, let alone to perform long-term clinical trials utilizing these specific diets or dietary patterns. Thus, although data from interventional studies have started to emerge, current dietary recommendations are based mainly on expert opinion, based, to a large extent, on observational studies (which do not prove causality), expected outcomes and risk–benefit estimations.
We discuss herein the effects of different treatment modalities, including behavioral modiﬁcations such as diet and exercise, pharmacotherapy, and bariatric surgery, on obesity and its comorbidities, including cardiovascular risk factors, risk for malignancy, bone disease, biliary disease, and overall quality of life. Pertinent randomized controlled clinical trial and meta-analysis data are discussed and when these are not available, or do not fully elucidate relevant questions, data from observational studies and case series are reported in the relevant chapters of this book.
6. WHERE WOULD WE LIKE TO BE IN THE NOT SO DISTANT FUTURE?
In energy deficiency states we clearly need to advance further our understanding of the role of leptin (and other hormones) to improve and/or correct the neuroendocrine abnormalities of women with hypothalamic amenorrhea and anorexia nervosa as well as those of obese subjects dieting to lose weight and/or having had surgery for obesity. We also need conclusive evidence from randomized trials on whether leptin and/or other treatment options could also improve the osteoporosis of subjects with anorexia nervosa or hypothalamic amenorrhea. Importantly, we need to learn whether the effect of leptin in improving neuroendocrine function could facilitate weight maintenance of obese subjects who strive to lose weight. Much needed investigations are underway in this area.
With obesity affecting greater numbers of people each year and with currently available methods having only modest success to reduce the increasing prevalence of obesity, there is an urgent need to develop better weight loss and weight maintenance programs. We also need to clearly identify the many genetic and environmental components that are involved in the pathogenesis of the problem and to carefully study the underlying molecular, cellular, and hormonal mechanisms. On the basis of elucidating these factors, effective diagnostic tools and pharmaceuticals could hopefully be designed, appropriate behavioral modiﬁcation programs could be investigated, and well-informed public health(Buy now from http://www.drugswell.com) recommendations could be formulated to direct and implement pervasive, effective, and enduring changes to the ways we live our lives.
Diet and exercise are the cornerstones of prevention and treatment of obesity and related disorders. Although dietary recommendations have been changing over the past few years, it is hoped that, as we learn more from both observational and interventional studies, our recommendations will continue to be refined and will hopefully prove to be more and more effective. It is also hoped that diagnostic and therapeutic methods will continue to improve significantly. New medications and new surgical methods are continually tested, developed, and applied. We present herein our current understanding of underlying scientific principles and current recommendations with the explicit understanding that medical approaches should not only be characterized by continuous quality improvements but need to also be individualized and guided by the responsible treating physician.
Each chapter in this book provides an authoritative review of the current status of research and knowledge in each one of the most important clusters of current work in the Nutrition and Metabolism ﬁeld. Text and graphs of several chapters appeared in their original form in the textbook “Nutrition and Metabolism”, C. Mantzoros (editor), published by the Aristides Daskalopoulos Foundation in Athens, Greece, 2007. Material from these chapters is reproduced herein with permission granted by the Aristides Daskalopoulos Foundation. The chapters in this book are relatively brief, analytical, based on scientiﬁ c evidence, and are written in an accessible style. We all hope that putting together cutting-edge research and reviewing critically current knowledge in all these ﬁelds will result in a sum that will be greater than its individual components. We also hope that ongoing work will lead, in the not so distant future, to a better understanding of the problems we are facing and to a more efﬁcient creation of novel solutions that would allow us to effectively combat and hopefully eliminate this epidemic of the twenty-ﬁrst century.
Key Words: Mutations, Polymorphisms, Chromosomal loci, Animal models
Obesity is a complex trait with multifactorial etiology, including environmental, behavioral, and genetic factors. The genetic contribution to human body weight has been established through family studies, investigations of parent–offspring relationships, and the study of twins and adopted children (1,2). The estimated heritability for body weight is 40–70% (3). Although obesity was first considered to be a disease that obeys Mendelian inheritance, the application of continuously evolving molecular biology technologies
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_2, © Humana Press, a part of Springer Science + Business Media, LLC 2009
has revealed a far more complex picture for this metabolic disease and has led to fascinating new developments.
The contribution of genetic factors to obesity can be either a single, dysfunctional gene (monogenic obesity) or, as in the case of common (polygenic) obesity, numerous genes that make up minor contributions in determining the phenotype.
In general, the two methods used for the study of genetic factors in complex diseases include the candidate gene approach and the genome-wide scan approach. The candidate gene approach examines the association of a given allele and the presence of the disease, while the genome-wide scan, or linkage analysis, locates genes through their genomic position and is based on the rationale that family members sharing a speciﬁ c phenotype will also share chromosomal regions surrounding the gene involved. Linkage and linkage disequilibrium analysis in speciﬁc rely on the fact that genes with similar chromosome positions will only rarely be separated during genetic recombination, so susceptibility to causative genes can be localized by searching for genetic markers that cosegregate.
In addition to genetic studies in human families, the existence of naturally or genetically modiﬁed animal models has provided valuable information on our understanding of the pathophysiology of disease. The mouse represents the most frequently used species for the creation of transgenic or gene knockout animals, allowing the analysis of the effects of gene overexpression, modiﬁcation, or deletion. Rats are also used for transgenic studies, but this animal model has practical and technical disadvantages over the mouse model and hence is less frequently used. Transgenic animal models provide critical tools for in vivo functional characterization of single genes and for the search of unknown genes implicated in disease manifestation. Nevertheless, there are also limitations that call for great care in interpreting results from transgenic animal models and in translating them to humans. For example, loss or overexpression of individual proteins may produce compensatory mechanisms that could mask the resulting phenotype. Most important however, the phenotypic or pathophysiological consequences of genetic manipulation in animal models may not always match the human disease (4).
Initial knowledge on the genetic involvement in monogenic obesity was derived from large-scale linkage analysis in obese mice carrying naturally occurring mutations. These analyses have pointed to disease-related loci and have identified the majority of gene mutations leading to monogenic obesity in mice (3). In particular, the genetic characterization of naturally occurring obese animal models, such as ob/ob, db/db, fat and tubby mice, led to the discovery of recessive mutations in the genes encoding leptin (Lep or ob), leptin receptor (Lepr or db), carboxypeptidase E (Cpe, or fat), and tubby (Tub) (5,6). Furthermore, the latest murine obesity gene map identified 248 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes affecting body weight and adiposity (7). Transfer of this knowledge to clinical cases has confirmed the role of the above genes in human monogenic obesity and uncovered the critical role of the leptin/melanocortin pathway in the regulation of energy homeostasis (8). Briefly, this hypothalamic pathway is activated following the systemic release of leptin and its subsequent interaction with the leptin receptor located on the surface of neurons of the arcuate nucleus of the hypothalamus. The downstream signals that regulate energy homeostasis are then propagated via proopiomelanocorin (POMC), cocaine- and amphitamine-related transcript (CART) and the melanocortin system (9,10) . While POMC/CART neurons synthesize the anorectic peptide α -melanocyte-stimulating hormone (α-MSH), a separate group of neurons express the orexigenic neuropeptide Y (NPY) and the agouti-related protein, which acts as a potent inhibitor of melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R).
To date, mutations in 11 different genes (Table 1 ), including LEP, LEPR, POMC, and proconvertase 1 (PC1), have been linked to obesity, in nearly 200 patients (7,30). Patients with monogenic obesity have extremely severe phenotypes that present in childhood and are often associated with additional behavioral, developmental, and endocrine disorders (31). MC4R-linked obesity represents the most prevalent form of
Genes Implicated in Monogenic Obesity
|Leptin Leptin receptor Proopiomelanocortin||LEPLEPRPOMC||7q31.3 1q31 2p23.3||Recessive Recessive Recessive||Severe, from ﬁ rst days of life Severe, from ﬁ rst days of life Severe, from ﬁ rst month of life||11–13 14, 15 16, 17|
|Proconvertase 1||PC1||5q15–q21||Recessive||Considerable, from ﬁrst month of life||18|
|Melanocortin-4receptor Single-minded homolog 1||MC4RSIM1||18q22 6q16.3–q21||Dominant Dominant||Variable severity, early onset Severe, from childhood||19–22 23|
|Neurotropic||NTRK2||9q22.1||Dominant||Severe, from ﬁ rst||24|
|tyrosine kinase||months of life|
|receptor type 2|
|Corticotropin-re||CRHR1||17q12–q22||Dominant||Severe, early onset||25|
|mone receptor 1|
|Corticotropin-re||CRHR2||7p14.3||Not known Not known||25|
|mone receptor 2|
|G-protein-coupled||GPR24||22q13.3||Dominant||Severe, early onset||26|
|Melanocortin-3||MC3R||20q13.2||Dominant||Severe, early onset||27–29|
monogenic obesity identiﬁed to date, representing ~2–3% of childhood and adult obesity (30,32,33). MC4R is a G-protein-coupled receptor with seven transmembrane domains that plays an important role in controlling weight homeostasis (10). MC4R knockout mice develop morbid obesity and increased linear growth, whereas heterozygous mice are also obese but with a varying degree of severity (34). Investigations in the molecular mechanisms by which loss of function mutations in MC4R cause obesity have suggested a number of functional anomalies, including abnormal MC4R membrane expression, a defect in agonist response, and disruption in the intracellular transport of the protein (35). Other single gene mutations leading to obesity involve single-minded homolog 1 (SIM1), melanocortin receptor 3 (MC3R), and neurotrophic tyrosine kinase receptor type 2 (TRKB/NTRK2) (23,24,27).
The major goal of the extensive ongoing research is the development of therapies targeting monogenic obesity, in order to ameliorate the metabolic status of obese individuals. Leptin therapy, by subcutaneous injection of leptin in children and adults deﬁcient in this adipokine, markedly reduced their body weight, having a major effect on reducing food intake and on other dysfunctions, including immunity (36) . Although treatments are not available yet for cases of LEPR, POMC-, PC1-, SIM1-, MC4R-, and TRKB-linked obesity, preliminary studies suggest that targeted therapies could be possible to develop (37).
In addition to the monogenic forms of obesity, this phenotype is also associated with many genetic syndromes. Syndromic obesity was initially thought of as monogenic; however, the contribution of multiple genetic factors in a syndrome is significantly more challenging than localizing the single gene involved in monogenic disorders.
There are currently 20–30 Mendelian disorders in which, in addition to mental retardation, dysmorphic features, and organ-speciﬁc developmental abnormalities, patients are also clinically obese (30,31). Such cases are referred to as syndromic obesity. These syndromes arise from discrete genetic defects or chromosomal abnormalities and can be either autosomal or X-linked disorders. The most common disorders known are Prader– Willi syndrome (PWS), Bardet-Biedl syndrome (BBS), and Alström syndrome (38).
PWS, the most frequent of these syndromes (1 in 25,000 births), is characterized by obesity, hyperphagia, diminished fetal activity, mental retardation, and hypogonadism. PWS is caused by the absence of the paternal segment 15q11.2–q12, through chromosomal loss (39–41). Several candidate genes in this chromosomal region have been studied; however, the genetic basis of polyphagia remains undeﬁned because none of the PWS mouse models have an obese phenotype (42). One genetic candidate that may disrupt the control of food intake is the gastric hormone ghrelin, which could act through the regulation of hunger and stimulation of growth hormone (43).
BBS is characterized by early onset obesity, retinal dystrophy, morphological ﬁ nger abnormalities, mental disabilities, and kidney diseases (44,45). To date, BBS has been associated with at least 12 distinct chromosomal locations, with several mutations identiﬁed so far (46–57). Although the precise function of the BBS proteins is yet to be determined, current data support a role in cilia function and intraﬂ agellar transport (58–60).
Alström syndrome is a very rare disorder, which in addition to obesity, is associated with congenital retinal cone dystrophy, cardiomyopathy, and type 2 diabetes (61,62) . Family studies have identiﬁed several mutations in the Alström syndrome 1 gene ( ALMS1 ), the majority of which are nonsense and frameshift (insertion or deletion) mutations predicted to lead to premature protein termination (63–65). ALMS1 is a ubiquitously expressed protein with recently proposed functional involvement in cilia formation (66,67).
As the above genetic syndromes involving obesity are rare, their underlying genetic involvement has been difﬁcult to decipher. Furthermore, even in the cases where the responsible genes have been identiﬁed, the pathophysiological link between the protein products and the development of the disease has not yet been fully elucidated.
Polygenic, or common, obesity arises when an individual’s genetic makeup is susceptible to an environment that promotes energy intake over energy expenditure. Specifically, environments in most westernized societies favor weight gain rather than loss because of food abundance and lack of physical activity, thus rendering common obesity as a major epidemic currently challenging the medical and financial resources in these societies (37).
A range of polygenic mouse models have been generated through inbreeding of mouse lines or repeated selections of noninbred mice, and have enabled the identiﬁ cation of >408 quantitative trait loci (QTL) associated with obesity ( http://obesitygene. pbrc.edu ). A recent meta-analysis of ~280 QTL, from 34 mouse cross-breeding experiments involving >14,500 mice, revealed 58 QTL regions associated with body weight and adiposity ( http://www.obesitygenes.org ) (68). Different QTL have been associated with the age of onset and gender in obesity, while certain loci may only contribute to obesity by interacting with other loci (69).
In humans, studies of polygenic obesity are based on the analysis of single nucleotide polymorphisms (SNPs) or repetition of bases (polyCAs or microsatellites) located within or near a candidate gene. These studies are carried out in family members (family study) or unrelated individuals (case–control study), and their objective is to determine a potential association between a gene’s allelic variant and obesity-related traits (70). However, unlike monogenic obesity, many genes and chromosomal regions contribute to the common obese phenotype (7,71). For this purpose, large DNA banks have been established from different populations throughout the world and are used for the extensive investigation of large number of genes and chromosomal regions. The ﬁndings of these genetic studies are reported every year by the Human Obesity Gene Map consortium. According to their latest report, 253 QTL have been identiﬁ ed, in 61 genome-wide scans (7). All chromosomes, except the Y chromosome, have been found linked with an obesity-related phenotype, such as fat mass, distribution of adipose tissue, resting energy expenditure, or levels of circulating leptin and insulin. Genes associated with obesity include solute carrier family 6 (neurotransmitter transporter) member 14 (SLC6A14), glutamate decarboxylase 2 (GAD2), and ectonucleotide pyrophosphatase/ phosphodiesterase I (ENPPI) (72–74). These genes have been implicated in a variety of biological functions such as the regulation of food intake, energy expenditure, lipid and glucose metabolism, adipose tissue development, and inﬂammatory processes. Recent genome-wide association studies have identiﬁed genetic variants (SNPs) associated with obesity-related traits in both children and adults, in the fat mass and obesity associated (FTO) gene (75–77, 272). It has been proposed that through its catalytic activity, FTO may regulate the transcription of genes involved in metabolism (78).
In contrast to genetically identical mice, whose environments can be controlled, the genetic and environmental diversity in humans has proved problematic for data replication. To date, only 22 obesity-related genes are supported by at least ﬁve positive studies (7,37). The reasons for the lack of replication in association and linkage studies include lack of statistical power to detect modest effect, lack of control over type I error rate, and overinterpretation of marginal data (79). Thus, the use of novel approaches may provide the means to circumvent classical statistical obstacles in identifying new candidate genes and possible gene–environment interactions (see Sect. 4).
The immense ongoing research on the identiﬁcation of new molecular targets for antiobesity drugs and the signiﬁcance of the generated ﬁndings is reﬂected by the rapidly increasing number of patent applications. Speciﬁcally, a total of 173 US patents were issued between January 2001 and March 2004, with the word “obesity” included in the abstract (80,81). Among the molecular targets with the highest number of new patents are the serotonin receptor ligands (24 patents), neuropeptide Y receptor ligands (20 patents), and adrenergic receptor ligands (20 patents).
The term metabolic syndrome (occasionally called insulin resistance syndrome) refers to a constellation of clinical findings including obesity, hypertension, hyperlipidemia, and insulin resistance, with increased risk for type 2 diabetes and cardiovascular disease. It has also been linked with chronic kidney disease, liver disease with steatosis, fibrosis, and cirrhosis, and cognitive decline and dementia. Despite recent controversy regarding the concept of a metabolic syndrome, the International Diabetes Federation (IDF) developed a new unifying worldwide definition building upon the World health(Buy now from http://www.drugswell.com) Organization (WHO) and ATP III definitions, as will be discussed in later chapters (82).
On the basis of the IDF deﬁnition, almost 40% of US adults are classiﬁed as having the metabolic syndrome (83). Although environmental factors such as smoking, low economic status, high intake of carbohydrates, no alcohol consumption, and physical inactivity can play a role in the development of the metabolic syndrome, a series of evidence indicates that there is also a genetic component involved. Speciﬁcally the metabolic syndrome has different prevalence between men and women, and among ethnic groups, as well as different concordance rates between monozygotic twins. Furthermore, there is increased incidence in individuals with a parental history of metabolic syndrome, and a general familial clustering of the metabolic syndrome and its components (83–91).
Ongoing work on spontaneous and engineered animal models has revealed that several genetic loci are associated with metabolic syndrome components in different rodent models (92). Examples of metabolic syndrome rodent models include the spontaneous hypertensive rat (SHR), the transgenic SHR overexpressing a dominant-positive form of the human sterol regulatory element binding transcription factor 1 (SREBP-1), the SHR/ NDmcr-cp rat, the polydactylous rat strain (PD/cub), the obese Zucker rats (OZR), the New Zealand obese (NZO), the Wistar Ottawa Karlsburg W rats, as well as congenic, consomic, and double-introgressed strains (93–100).
Linkage analyses in patients with the metabolic syndrome have aimed at identifying loci with pleiotropic effects on multiple aspects of the syndrome. Several different linkage analysis approaches have been applied in the study of the metabolic syndrome, such as principal components or principal factor analysis, multivariate analysis, metabolic syndrome score from combined residuals and the structural equation model (101). One of the most consistent ﬁndings was the linkage to chromosome 1q, while multiple phenotypes linked to this region indicate that it likely harbors a gene with pleiotropic effects on measure of glucose, lipids, hypertension, and adipocity, or multiple genes that contribute to each one of these features (102–106). Other consistent loci implicated in the development of the metabolic syndrome include chromosomes 2p, 2q, 3p, 6q, 7q, 9q, and 15q (103,106–111).
Many of these loci have also been linked to individual components of the metabolic syndrome. For example, chromosome 2p has been linked to serum triglycerides, systolic blood pressure, obesity, body fat percentage, and HDL (111–113) , while chromosome 7q has been linked to systolic blood pressure, triglyceride–HDL-C ratio, fasting glucose, insulin, and insulin resistance (114–116).
Despite the wide use and important ﬁndings that have emerged from linkage analysis, this method presents with a number of limitations that need to be carefully considered and addressed in the interpretation of current ﬁndings and the design of future studies. Some of the common obstacles in this type of studies are the inadequate statistical power, the multiple hypothesis testing, the population stratiﬁcation, the publication bias and phenotypic variation (117) . The identiﬁcation of true genetic associations in common multifactorial conditions, such as the metabolic syndrome, requires large studies consisting of thousands of subjects. This need is further accentuated by the large number of implicated genetic loci and their potentially small contribution to the phenotype when individually considered.
In parallel to linkage and association studies, several studies have evaluated the contribution of speciﬁc candidate genes to the metabolic syndrome pathogenesis. These candidate genes have been selected based on their biological function and/or previous associations to any of the phenotypic aspects of the syndrome. However, the large number of metabolic pathways implicated in the pathogenesis of the metabolic syndrome (including insulin signaling, glucose homeostasis, lipoprotein metabolism, adipogenesis, inﬂammation, coagulation, etc.) renders this search a highly challenging task that has yielded a relatively limited success. There are many examples of genes directly or indirectly implicated in the development of the metabolic syndrome or speciﬁc clinical features related to it, but an equal number of negative studies have also been published (118).
The peroxisome proliferator-activated receptor γ (PPAR g) is one of the strong candidates for conferring susceptibility to the metabolic syndrome because of its involvement in adipocyte differentiation, fatty acid metabolism, insulin sensitivity, and glucose homeostasis (119–121). Despite some inconsistencies in the PPAR γ association studies, the overall evidence seems to suggest that PPAR g polymorphisms can increase the risk for developing the metabolic syndrome (122–124). Direct correlations to the metabolic syndrome have also been described for genetic variants of the β3 -adrenergic receptor (ADRb-3), nitric oxide synthase 3 (NOS3), angiotensin I converting enzyme (ACE), beacon (BEACON), lamin A/C ( LMNA), interleukin-6 (IL-6 ), interleukin- β (IL1-b ), and protein tyrosine phosphatase nonreceptor type 1 (PTPN1) genes (122,125–131) . Interestingly, PPAR g and IL1-b polymorphisms have been implicated in gene–environment interactions (see Sect. 4 ).
Fatty acid binding protein 2 (FABP2) and apolipoprotein C-III (APOC3 ) polymorphisms have been directly associated with increased risk for dyslipidemia and the metabolic syndrome in Asian-Indians (132). Other examples include a number of lipid-sensitive transcription factors (nuclear receptor subfamily 1, member 4 (FXR ), nuclear receptor subfamily 1, member 3 (LXR-a), retinoid X receptor α (RXR-a), PPAR- a, PPAR- d, peroxisome proliferator-activated receptor ( PGC1-a), PCG1-b, sterol regulatory element binding transcription factor 1 (SREBP-1c)) that have been implicated in the development of dyslipidemia, one of the very early features of the metabolic syndrome (124). Since lipoprotein metabolism plays a central role in the metabolic syndrome, several genes related to the former are also good candidates for the latter. These include variants of scavenger receptor class B, member 1 (SCARB1 ), ATP-binding cassette subfamily A, member 1 ( ABCA1), cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL), lipase (LIPG), pancreatic lipase (PNLIP ), apolipoprotein A-V (APOA5), and the apolipoprotein gene clusters ApoA1/C3/A4/A5 and ApoE/C1/C2 that affect HDL-cholesterol and triaglyceride metabolism (133–138).
Hypertension is one of the components of the metabolic syndrome and a major risk factor for cardiovascular disease. Similar to obesity and the metabolic syndrome, hypertension seems to be the outcome of combined genetic and environmental etiologies (139). Mutations in eight genes have been identified to cause severe but rare forms of monogenic hypertension (140). Interestingly, all of these genes participate in the same physiological pathway in the kidney, altering net renal salt reabsorption. However, the genetic factors behind the common, less severe forms of hypertension, collectively termed essential hypertension (i.e., hypertension with unknown cause), are poorly understood. A large number of candidate gene, linkage, and association studies have sporadically implicated a range of different genetic loci in hypertension development. Polymorphisms in the angiotensinogen (AGT), the natriuretic peptide receptor A ( NRP1), and ACE are prime examples of the most consistent findings in the literature (141–144) . Nonetheless, genome-wide linkage analyses have not consistently implicated specific chromosomal loci, suggesting a model in which there may be many loci, each imparting small effects on hypertension in the general population (145–148). Similar to other multifactorial diseases, the study of hypertension in humans will require the consistent replication of results in large and rigorously characterized populations that are well suited for detecting alleles imparting small effects. Such populations would include cohorts of unrelated individuals as well as family-based linkage disequilibrium studies. These latter tests minimize the chance of false-positive associations arising from population admixture of individuals of different genetic backgrounds (149). Meta-analysis of the combined results from multiple different studies/populations can also greatly contribute towards this end, as for example in the case of a methylenetetrahydrofolate reductase (MTHFR) polymorphism that appears to be significantly associated with hypertension in multiple populations (150).
In parallel to human studies, a series of spontaneous and engineered animal models of hypertension have been extensively studied. For example, inbred rat strains that display hypertension as an inherited trait have long been used as a means for identifying genes that can give rise to essential hypertension. Examples of these strains include SHRs, Dahl salt-sensitive rats, Sabra hypertensive-prone rats, Molan, Lyon, fawn-hooded and Prague hypertensive rats (151). Importantly, some of the ﬁ ndings in these animal models have later been translated to humans, such as in the case of brain and muscle Arnt-like protein-1 ( Bmal1) polymorphisms which are associated with susceptibility to hypertension and type 2 diabetes (152). Congenic and consomic rat strains have also been used to identify QTL for hypertension, in an effort to eliminate the variability arising from the often heterogeneous genetic background of these animals (151,153–157). In support of the notion that hypertension is a polygenic condition, at least one blood-pressure-related QTL has been identiﬁed on almost all rat chromosomes (151). Genetically engineering mouse models with increased or decreased expression of targeted genes has also provided useful insights (158) . For example, deletions of various genes (including the bradykinin B2 receptor, D1A and D3 dopamine receptors, atrial natriuretic peptide, endothelial nitric oxide synthase, and others) have resulted in elevated blood pressure, while in other cases, gene mutations have had little or no effect (159–163). Furthermore, mouse models have enabled the conﬁrmation of various observations in humans, and the more detailed characterization of the disease physiology (158).
Diabetes mellitus represents a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The pathogenic processes involved in the development of diabetes range from autoimmune destruction of the pancreatic β cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action (164). There are two main etiopathogenetic categories of diabetes: (1) type 1 diabetes, which is caused by deficiency of insulin secretion and rises independently of obesity or the metabolic syndrome (will be covered in Sect. 3 ), and
(2) type 2 diabetes, which is caused by a combination of resistance to insulin action and inadequate compensatory insulin secretion. Type 2 diabetes, or noninsulin-dependent diabetes mellitus, is the most frequent form of diabetes, accounting for 90% of the disease prevalence, with an estimated 150 million affected people worldwide (165,166). Overall, type 2 diabetes is characterized by impairment of insulin secretion and decrease in insulin sensitivity. Initial studies in families with rare monogenic forms of diabetes pointed towards a genetic component of type 2 diabetes (167). However, it has become evident that the incidence of the disease is also affected by environmental influences, such as lifestyle and diet.
On the basis of the role of genetic factors, type 2 diabetes may be divided into monogenic and polygenic forms, where monogenic forms are the consequence of rare mutations in a single gene whereas polygenic forms are the result of the interaction between the environment and genetic contribution of many different genes (168,169).
Polygenic, or the common form, type 2 diabetes is a complex and heterogeneous disorder that is influenced by the contribution/impact of multiple genes and various environmental factors that can affect disease predisposition. In many cases obesity and the metabolic syndrome precede the development of type 2 diabetes. Owing to its complexity, with both gene–gene and gene–environment interactions, the genetic influences on this form of type 2 diabetes have been difficult to elucidate and the identification of genes has not been easily achieved (Fig. 1 ).
Animal models for type 2 diabetes have enabled the study of the molecular pathways involved in disease pathophysiology, providing useful information on the molecular etiology of type 2 diabetes and pointing towards potential therapeutic interventions. The numerous spontaneous animal models for type 2 diabetes have facilitated our understanding of disease physiology and have aided towards the identiﬁcation of underlying genetic factors. Examples of such models include the Nagoya-Shibata-Yasuda (NSY) mouse model, which spontaneously develops diabetes in an age-dependent manner, the diabetic db/db mice and the KK mouse strain, which shows inherently glucose intolerance and insulin resistance (170–172). Additional spontaneous animal models presenting insulin resistance and impaired insulin secretion include the Goto Kakizaki rat, the Otsuka Long-Evans Tokushima fatty (OLETF) rat and the Zucker Diabetic Fatty rat model (173–175). Genome-wide linkage scans in OLETF rats have identiﬁed susceptibility loci on chromosomes 1, 7, 14, and the X chromosome, while a sequence variation in the hepatocyte nuclear factor 1β (Hnf1b), a gene implicated in human MODY (maturity-onset diabetes of the young) disease, was identiﬁed in the NSY mouse model (176–178).
In addition to spontaneous animal models, an increasing number of genetically engineered models have been generated for type 2 diabetes. In an attempt to recreate the human disease in animals, investigations have focused on the understanding of β-cell dysfunction or insulin resistance pathways. Depending on the targeted protein and its importance on insulin signaling, various degrees of insulin resistance can be created. Insulin-receptor (IRS)-deﬁcient mice were among the ﬁrst knockout mice to be generated with affected proteins in the insulin signaling cascade. Heterozygous mice exhibit normal glucose tolerance and only 10% of adult animals develop diabetes, while homozygous
Fig. 1. Progress in the identiﬁ cation of susceptibility genes for type 1 and type 2 diabetes over the past decade.
IRS-deﬁcient mice rapidly develop diabetes and die within 3–7 days after birth, thus demonstrating the essential role of IRS in the control of glucose metabolism (179,180). Deﬁciency of the insulin receptor substrate 1 protein (IRS-1) in mice results in postnatal growth retardation with only mild insulin resistance and no diabetes, whereas deletion of IRS-2 causes impaired insulin signaling and β-cell function, resulting in progressive deterioration of glucose metabolism (181,182). On the other hand, IRS-3 and IRS-4 knockout mice show respectively either mild glucose intolerance or have no phenotype, therefore suggesting that they are unlikely to play a major role in glucose homeostasis (183,184).
In an attempt to resemble the polygenic nature of type 2 diabetes, polygenic animal models containing combined gene disruptions have been created. Double heterozygous mice for IRS and IRS-1 exhibit a synergistic impairment on insulin action, presenting a phenotype that is much stronger than individual gene deﬁ ciency (185). In contrast to their respective individual gene deﬁciency models, double knockout mice for IRS-1 and β-cell glucokinase (Gck) develop overt diabetes, demonstrating that combination of minor mutations in genes involved in either insulin action alone or insulin secretion and action can cause diabetes (186). Overall, polygenic mouse models have demonstrated that, when combined, minor defects in insulin secretion and action can lead to diabetes, therefore emphasizing the interaction between different genetic loci in diabetes.
Animal models with tissue-speciﬁ c inactivation of insulin receptor genes have also been generated, in order to assess insulin action in individual tissues. These include the muscle-speciﬁc insulin receptor knockout mice, the liver insulin receptor knockout mice, and the β-cell insulin receptor knockout mice (187–189). Such tissue-speciﬁ c models have helped in dissecting the contribution of individual insulin-responsive organs to glucose metabolism.
In humans, candidate gene analyses towards the identiﬁ cation of type-2–diabetesrelated genes have focused on genes implicated in insulin resistance and particularly in β-cell development, insulin signaling, or hypothalamic regulation. This has included genes such as the PPAR g, the ATP-binding cassette subfamily C member 8 ( ABCC8 ) and potassium-inward rectiﬁer 6.2 ( KCJN11), and IRS-1 (119,190) . The best-characterized and most robust variant is the highly prevalent Pro21Ala polymorphism in PPAR g . Two meta-analyses have shown that the proline allele, which is the most frequent allele, is associated with a moderate increase in risk for type 2 diabetes. Furthermore, a 21–27% risk reduction was shown for the presence of the alanine allele, hence suggesting that the alanine genotype results in greater insulin sensitivity (191–193) .Other meta-analyses studies have determined that in the KCJN11 gene, which encodes the ATP-sensitive potassium channel subunit Kir6.2, the frequent variant E23K shows association with a slightly increased susceptibility to type 2 diabetes in some populations, with the risk for the disease increasing by about 15% in the presence of the K allele (190,194) . However, in many cases the initial associations have not been replicated in subsequent studies. For example, a meta-analysis of ~9,000 individuals initially determined that the G971R variant in IRS-1 had a signiﬁcant effect on diabetes risk; however, two subsequent studies failed to conﬁrm this association (195–197).
To date, more that 50 linkage studies have been conducted in a variety of populations. Although initially the regions of linkage determined by the different studies were inconsistent (because of differences in study design, family conﬁ guration, ethnic heterogeneity), the completion of additional scans revealed that some chromosomal regions, and in particular chromosomes 1q21–24, 1q31–q42, 9q21, 10q23, 11p15, 12q12, 19q13, and 20q11–q13, are showing positive association with the disease in more than one study (198). Calpain 10 (CAPN10) was the ﬁrst polygenic diabetes gene to be cloned
(199) and it encodes for a ubiquitously expressed cysteine protease. Although widespread acceptance of CAPN10 as a type-2-diabetes-predisposing gene was not initially achieved, recent studies have provided further evidence for the biological importance of CAPN10 variation in susceptibility for the disease. A meta-analysis of more than 7,500 patients of diverse ethnic origin has determined a signiﬁcant association for the presence of a CAPN10 variant (SNP-44; CAPN10-g4841 T → C) and the disease (200) . It has been proposed that genetic variants of CAPN10 might affect insulin sensitivity, insulin secretion, or the relation between the two (201–203). Other genes associated with the common form of type 2 diabetes include transcription factor 7-like 2 gene (TCF7L2) (204,205), FTO (77,206,273), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), genetic variants of which impair insulin binding to its receptor in muscle and brain, hence leading to fat deposition (207).
The shape of genetic association studies for type 2 diabetes is set to be transformed in the next few years, with the advent of truly genome-wide association scans. The availability of array-based platforms that will allow the performance of massive parallel genotyping (between 250,000 and 1 million SNPs per assay), combined with the information provided by the International HapMap Consortium, will provide powerful means for a global view of genetic associations in type 2 diabetes (208). Indeed, through the simultaneous analysis of thousands of genetic variants (SNPs) in large diabetes patient cohorts, genome-wide association studies have recently identiﬁed the solute carrier family 30 member 8 (SLC30A8), the insulin degrading enzyme (IDE), and hematopoetically expressed homeodomain HHEX (HHEX/IDE) genes, as well as the cyclin-dependent kinase 5 (CDK5) regulatory subunit associated protein-1-like 1 (CDKAL1) melatonin receptor 1B (MTNR1B) (274), the insulin-like growth factor 2 mRNA binding protein (IGF2BP2), and the cyclin-dependent kinase inhibitor 2A ( CDKN2A) genes as type 2 diabetes susceptibility genes (204,206, 209, 210). However, as these loci explain a small proportion of the observed familial cases of the disease, it is expected that additional loci will be revealed in the near future by further systematic screens (211).
Our understanding of the molecular pathways involved in the pathogenesis of the disease could also be enhanced by the utilization of novel technologies. For example, the microarray technology has been used to identify differential mRNA expression patterns in muscle tissue of type 2 diabetes patients and normal controls (212) . The application of metabolomics, which is deﬁned as the measurement of all metabolites present within a cell, tissue, or organism following genetic medication or physiological stimulus, will also contribute valuable insights into the understanding of the pathophysiology of the disease as it provides the potential of globally proﬁling the metabolome of an organism (213,214). Although few studies of metabolomics have focused on diabetes, a recent application of the technology to type 2 diabetes has identiﬁed characteristic alterations in the plasma phospholipids proﬁle, therefore enabling the identiﬁcation of patients from control individuals (215,216).
The monogenic form of type 2 diabetes constitutes a small group accounting for ~5% of the disease and is characterized by high phenotypic penetrance, early disease onset, and often a severe clinical picture (69,168,169). The most frequent monogenic type 2 diabetes form is the autosomal dominant MODY, a term that was first used by Tattersall and Fajans in 1975 (217). So far, six genes responsible for MODY have been described, and they include hepatocyte nuclear factor-4 α , -1 α , -1 β (HNF-4a, -1a, -1b), GCK , insulin promoter factor 1α (IPF-1a), and neurogenic differentiation 1 ( NEUROD1) (218–223). All of the MODY genes are expressed in the pancreatic β-cells, and, with the exception of GCK, all code for transcription factors with a role in β-cell development and function (224). Moreover, these MODY genes are functionally related, forming part of an integrated transcriptional network. However, as in 16–45% of MODY families, termed MODY X, there have been no mutations detected in any of the known MODY genes, it has been proposed that additional MODY genes could exist (225,226). In addition to the established MODY genes, mutations in familial diabetes have been implicated in two other genes, mitogen-activated protein kinase 8 interacting protein 1 (MAPK8IP1), which codes for another β-cell transcription factor, and ABCC8, the gene that codes for SUR1 (227,228).
Another monogenic form of type 2 diabetes, with distinct molecular involvement, is the maternally inherited diabetes. This is a very rare form of the disease that is caused by mutations in mitochondrial DNA, most often by mutations in the tRNA for leucine (229). Maternally inherited diabetes is associated with deafness (maternally inherited diabetes with deafness) or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) (230,231). Mitochondrial mutations could perturb glucose homeostasis/metabolism through impairment of the glucosensory function of the β cells and their decreased ability for insulin production (232).
Insulin-dependent diabetes mellitus (IDDM), or type 1 diabetes, is characterized by autoimmune destruction of insulin-producing β cells in the pancreas and severe insulin deficiency (233). Type 1 diabetes accounts for around 10% of all cases of diabetes, occurs more frequently in people of European descent, and affects 2 million people in Europe and North America (234). Currently, there is a 3% global increase in incidence per year, but this is predicted to increase considerably within the next few years (235).
Type 1 diabetes is a complex trait, the etiology of which has only been partially characterized. It is generally recognized though that the disease has both genetic (Fig. 1 ) and environmental inﬂuences. The advances in our understanding of the pathophysiology and the genetic factors underlying type 1 diabetes have beneﬁ ted immensely from studies on spontaneous or genetically manipulated animal models of the disease. Autoimmune diabetes in such models shares many molecular and genetic characteristics to human type 1 diabetes. Animal models have therefore provided valuable information that can be applied on studies of human type-1-diabetes-associated molecular and cellular pathways. The nonobese diabetic (NOD) mouse represents the most studied animal model for type 1 diabetes and has been utilized for the determination of over 20 non-HLA regions (known as insulin-dependent diabetes, Idd) associated with disease risk in this diabetic mouse strain (236). By narrowing down genetic intervals in animal models, a small number of candidate genes have been highlighted for association testing in human patients. An example of this is illustrated by the IL-2 pathway, which was considered as a candidate for the Idd3 locus in the nonobese diabetic mouse. Following extensive investigation, its involvement in human disease was revealed. Analysis of its orthologue gene in humans conﬁrmed its association in type 1 diabetes, therefore providing an example where genes discovered in animal models can be considered as primary candidates for investigation in humans (236). Other widely used animal models include the BioBreeding diabetes-prone rat and the Komeda diabetes-prone rat (237) . In addition to the naturally occurring animal models, a range of transgenic animals have been generated for a long series of different genes, including major histocompatibility molecules (e.g., D57, HLA-DRa , HLA-DQ6 ), cytokines (Il2, Tnfα, Tgfβ1 ), autoantigens (proinsulin, HSP60, GAD), costimulatory molecules (Cd152, Cd80), and T-cell receptors (BDC2.5, 8.3) (69).
Through association studies and linkage analysis in humans, an increasing number – 19 to date – of IDDM susceptibility loci have been identiﬁed (named by the abbreviation IDDM and a number reﬂecting the order with which they were reported, e.g., IDDM1, IDDM2, etc.) (69,238,239). The human leukocyte antigen (HLA) locus on chromosome 6p21 was the ﬁrst to be associated with the disease and is thought to contribute for around 50% of the familial basis of type 1 diabetes (234,240–242). It has been shown that the HLA-DR4-DQ8 and HLA-DR3-DQ2 haplotypes are present in 90% of children with type 1 diabetes, whereas HLA-DR15-DQ6 is found in only 1% of affected children but more than 20% in the general population, therefore suggesting that it is protective (243) . The genotype combining the two susceptibility haplotypes (DR4-DQ8/DR3-DQ2 ) contributes the greatest risk for the disease. Despite extensive research, the speciﬁc details as to how genes in this region modulate type 1 diabetes risk have still not been fully elucidated.
The insulin gene, or IDDM2 locus, on chromosome 11p15.5 was the second locus to be identiﬁed and is the second most common factor, contributing to 10% of the genetic susceptibility of type 1 diabetes (244). Susceptibility in the insulin gene has been primarily mapped to a variable number of tandem repeats located in the promoter region of the gene. Shorter forms of these repeats are associated with susceptibility to the diseases whereas longer repeats are associated with protection (245).
Other genes associated with type 1 diabetes include cytotoxic T-lymphocyte antigen 4 (CTLA4), protein tyrosine phosphatase, nonreceptor type 22 (PTPN22), small ubiquitin-like modiﬁer 4 ( SUMO4), and the α-chain of interleukin-2 receptor gene (IL2R) (246–248,275,276,277). The KIAA0350 gene, encoding for a protein with predicted sugar binding properties, was the latest one identiﬁ ed (249). Overall, a number of whole genome scans using families and affected sibling pairs performed over the past decade have provided evidence for the existence of many additional loci associated with type 1 diabetes, including but not limited to the IDDM loci (211,250–254,278).
In a coordinated effort on the analysis of existing type 1 diabetes families for the elucidation of the genetic etiology of the disease, the type 1 Diabetes Genetics Consortium (T1DGC) ( http://www.t1dgc.org ) has been established. The T1DGC represents a worldwide collaboration on the study of a large collection of patients and their families from around the world. The ﬁrst report from this consortium was published in 2005, and it included a combined linkage analysis of four datasets, three previously published genome scans, and a new dataset of 254 families (252). The T1DGC analysis included 1,435 families with 1,636 affected sibling pairs from the UK, the USA, and Scandinavia, representing one of the largest linkage studies performed so far. In addition to HLA, this large study determined evidence for linkage to ten other chromosomal regions. In particular chromosomes 2q31–q33, 6q21, 10p14–q11, and 16q22–24 showed genome-wide signiﬁcance, therefore indicating a strong non-HLA genetic contribution to type 1 diabetes (252).
The T1Dbase database ( http://T1DBase.org ) represents a powerful resource, which combines and organizes data for type 1 diabetes, focusing on the molecular genetics and biology of disease susceptibility and pathogenesis (255) . This public database allows scientists to search across different data sources/types, and thus find new relationships among factors contributing to the complex pathogenesis of type 1 diabetes (256).
In addition to the genetic contributions of type 1 diabetes, it is becoming evident that additional factors, such as environmental inﬂuences, are also involved in the development of the disease. Such factors include viruses, such as enteroviruses, rotavirus, and rubella (257,258). Nevertheless, even though Finland has effectively eradicated rubella through vaccination, it has one of the highest incidences of type 1 diabetes. This therefore supports the hygiene hypothesis, which proposes that environmental exposure to microbes early in life promotes innate immune responses that suppress atopy and autoimmunity. To address the role of environmental factors in type 1 diabetes, large-scale studies are required. For this purpose, the international consortium Environmental Determinants of Diabetes in the Young (TEDDY; http://www.niddk.nih. gov/patient/TEDDY/TEDDY.htm ) has been established so as to follow large number of babies with high-risk HLA genotypes during early life and thus identify infectious agents, dietary factors, or other environmental factors that could trigger autoimmunity in susceptible populations (234).
Even though, as described above, type 1 and type 2 diabetes represent two different disease entities, the clinical and etiological distinction between them is becoming more difficult as there is increasing evidence of a significant overlap between the two disease states. Clinical studies have reported that even within the same family both type 1 and type 2 diabetes may co-occur and patients with such double genetic predisposition have intermediate phenotype (259). As an example of common genetic predisposition, a variable number of tandem repeats polymorphism in the insulin gene promoter region has been associated with both type 1 and type 2 diabetes (259).
The “accelerator hypothesis” suggests that both type 1 and type 2 diabetes are the same disorder of insulin resistance set against different genetic background (260) . According to this hypothesis, type 1 and type 2 diabetes are one and the same entity, distinguished only by the rate of β cell loss. Instead of overlap between the two types of diabetes, the hypothesis envisages overlay between the two types, with one disease representing a subset of the other.
All evidence so far appears to support a shared genetic and environmental (with diet and exercise being among the most important) contribution to disease predisposition, including obesity, metabolic syndrome, and type 2 diabetes (Fig. 2 ). Nevertheless, the relative contribution of each of these two main parameters and the extent of their interaction are difficult to determine, and varies for each condition. It is noteworthy, that although the human genome has not changed significantly over the last few decades, the prevalence of obesity, metabolic syndrome, and type 2 diabetes are increasing exponentially. Although the genetic and environmental factors have long been studied independently, an increasing effort is now placed on deciphering the gene–environment interaction. Obesity, metabolic syndrome, and type 2 diabetes are classic examples of such gene– environment interactions (261–263). For example, in a cohort of 287 monozygotic and 189 dizygotic young adult male twin pairs, it was shown that sedentary twins were more likely to develop high waist circumference if they were genetically susceptible to obesity than if they were not (264). The complexity, however, of these multifactorial diseases has emphasized the need for development of more sophisticated statistical methods that would enable more accurate assessment of the interplay between complex combinations of multiple gene variants and environmental factors (265).
A large set of common genetic variants are currently under study in the European programs Nutrient–Gene Interactions in Human Obesity (NUGENOB) ( http://www. nugenob.com ) and Diet, Obesity and Genes (DIOGENES) ( http://www.diogenes-eu. org ). Such programs comprising both academic and industrial partners, aim to study gene–environment interactions and thus identify genetic determinants susceptible to environmental stimuli that are capable of inﬂuencing obesity development. Within these programs, the use of comprehensive platforms (i.e., genetics, transcriptomics, peptidomics, and metabolomics) coupled with clinical data will have a predominant role in elucidating the perturbed functions leading to obesity, and ultimately in developing better targeted therapies.
In the context of the metabolic syndrome development, a study of 303 elderly twin pairs recently showed that glucose intolerance, obesity, and low HDL-cholesterol concentrations are signiﬁcantly higher among monozygotic twins than among dizygotic twins,
Fig. 2. Genetic polymorphisms can affect predisposition to mutlifactorial diseases, such as obesity, on their own or in response to environmental factors, such as nutrition and exercise .
indicating a genetic inﬂuence on the development of these phenotypes. In contrast, the heritability estimates for hyperinsulinemia, hypertension, and hypertriacylglycerolemia are low, indicating a more important environmental inﬂuence on these components of the metabolic syndrome (266). Nevertheless, gene–environment interactions are slowly emerging for them too. For example, polymorphisms in endothelin 1 ( EDN1) are associated with increased risk for hypertension in low-ﬁt, but not in high-ﬁ t, white individuals (267).
Similar observations are emerging for the other multifactorial conditions described in this chapter, and they are likely to play a key role in addressing and reversing the current epidemic of obesity, metabolic syndrome, and type 2 diabetes.
One of the rapidly expanding scientific fields that address the way genes and bioactive food components interact is nutrigenomics. It specifically focuses on understanding how diet (1) affects the genome, directly (e.g. via methylation) or indirectly (e.g. at the gene expression level); (2) may compensate for or accentuate the effect of genetic polymorphisms; and (3) can alter the risk for disease development by interfering with the molecular processes involved in disease onset, incidence, progression, and/or severity. The ultimate goal is the in-depth understanding of the genome–nutrient interaction, which will lead to carefully targeted dietary intervention strategies for restoring health(Buy now from http://www.drugswell.com) and fitness and for preventing diet-related disease. Many studies are beginning to address the interplay between genome and nutrition, such as in the case of type 2 diabetes (268). A characteristic example of the importance of nutrigenomic studies lies in the discovery of a polymorphism in the angiotensinogen gene, which alters the effect of dietary fiber on human blood pressure. Specifically, individuals with the angiotensinogen TT genotype have decreased blood pressure, when provided with high insoluble fiber diets. In contrast, individuals with the TM or MM genotype do not experience a significant effect on their blood pressure in response to dietary fiber (269). Similarly, in individuals with a specific polymorphism in PPARgamma (Pro12Ala), a low polyunsaturated-to-saturated fat ratio is associated with an increase in body mass index and fasting insulin concentrations, suggesting that when the dietary polyunsaturated-to-saturated fat ratio is low, the body mass index in Ala carriers is greater than that in Pro homozygotes (270) . When the dietary ratio is high, the opposite is seen. Analysis of 1,120 white subjects in the context of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study demonstrated that common genetic variants at the IL1b locus were associated with risk of metabolic syndrome and related phenotypes. Importantly, a significant interaction was identified between dietary polyunsaturated fatty acids, and specifically docosahexaenoic acids and eicosapentaenoic acids, intake and the IL1b 6054G>A polymorphism, with AA subjects having significantly lower risk of metabolic syndrome. This suggests that the increasing genetic predisposition towards the development of metabolic syndrome in these individuals, could be reduced by a diet rich in polyunsaturated fatty acids, supporting the notion that more tailored dietary recommendations could be successfully used to prevent chronic diseases (131). Furthermore, the Framingham Heart Study, involving 2,148 participants, identified an APOA5 polymorphism that was associated with polyunsaturated fatty acid intake in a dose-dependent manner thus determining fasting triglyceride levels (271).
Current technological advances are enabling an unprecedented width and speed of scientific discovery, thus increasing rapidly our understanding of the genetic etiology of obesity, metabolic syndrome, and diabetes. Although the number of disease-associated genes has recently risen sharply, many more yet-to-be-discovered genes are believed to be implicated in the above-mentioned complex diseases. Better designed, large-scale, multipopulation meta-analyses are starting to provide the necessary statistical power and biological breadth to uncover new genetic players in disease development. In parallel to causative gene mutations and single nucleotide polymorphisms (SNPs – the most common form of polymorphisms associated with obesity, metabolic syndrome, and diabetes), new forms of genome variation such as DNA copy number variants or novel mechanisms of genome/transcriptome regulation, such as microRNAs, are introducing an additional level of complexity that needs to be considered. Advanced technological tools, together with cumulative biological knowledge, will allow us to answer the many open questions in disease pathophysiology such as, for example, the effect of type 1 diabetes genetic variants in immune response and tolerance or their role on insulin action and β -cell function in type 2 diabetes. Meanwhile, the long-suspected gene–environment interplay will be molecularly deciphered through rapidly evolving disciplines such as nutrigenomics. All this wealth of knowledge should translate in presymptomatic genetic diagnosis and effective preventive approaches, as well as improved clinical management when disease development is inevitable. Therapies will be better targeted to specific molecular pathways and therefore likely to be more efficient and effective. Ultimately, the advent of pharmacogenomics will allow the promise of personalized medicine to be fulfilled.
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Key Words: Body-weight homeostasis, Energy balance regulation , Obesity , Eating disorders
The incidences of both obesity and type 2 diabetes mellitus are rising at epidemic proportions and have emerged as a major threat to human health(Buy now from http://www.drugswell.com) in the late twentieth and early twenty-first century. Growing evidence suggests that nutrient and hormonal
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros (ed.), DOI: 10.1007/978-1-60327-453-1_3, © Humana Press, a part of Springer Science + Business Media, LLC 2009
signals converge and act directly on brain centers, leading to changes in fuel metabolism. Many newly discovered molecules that are proposed to play an active role in the physiology and pathophysiology of energy homeostasis have changed our understanding of obesity and metabolism and have attracted the attention of many researchers who strive to investigate and characterize the mechanisms underlying energy homeostasis. The purpose of this chapter is to summarize our current understanding of peripheral pathways regulating energy homeostasis and to outline new targets for the treatment of obesity, metabolic disorders, and associated comorbidities.
2. INPUTS IMPORTANT IN THE REGULATION OF ENERGY HOMEOSTASIS
Afferent signals to the brain convey information via exogenous and/or environmental factors influencing energy homeostasis, nutrients or metabolic factors, and finally hormonal signals regarding long- or short-term energy availability. These inputs can be classified into three distinct types, namely, neural environmental, nutrient/metabolic, and endocrine signals.
In modern societies of affluence, high palatability and orosensory properties of certain foods, in combination with environmental influences that promote a sedentary way of life, promote a positive energy balance and development of obesity. Mood and other signals that affect “emotional eating” and are being processed by complex neural circuits have a significant effect on these environmental signals and also regulate energy homeostasis.
Sensors expressed in hypothalamic neurons such as ion channels (1,2) and surface enzymes (3) act as direct sensors of nutrients such as carbohydrates and lipids and activate intracellular second messenger pathways to regulate energy homeostasis. The role of nutrients and metabolic signals to regulate energy homeostasis is discussed in detail below.
Hormones are released from peripheral endocrine organs, including the white adipose tissue (leptin), pancreas (insulin, amylin), stomach (ghrelin), and intestine (cholecystokinin, CCK). Hormonal signals such as the adipose-tissue-secreted hormone leptin and the pancreatic hormone insulin regulate the long-term metabolic status and body’s energy stores whereas other signals such as gastrointestinal hormones convey information on the amount or composition of the food entering the gastrointestinal tract.
Short-term regulation of feeding is also regulated by neural afferent signals from the periphery which are activated by a combination of mechanical stimuli (distension, contraction) (4), chemical stimuli (presence of nutrients in the gut lumen), and neurohumoral stimuli (gut hormones, neurotransmitters) (5) and are mainly conveyed via the vagus nerve to important CNS target centers such as the hypothalamus and the brain stem. The central integration of exogenous, environmental metabolic and peripherally secreted molecules by the CNS is discussed in detail in the subsequent chapter.
The rapidly changing environment and the associated lifestyle changes are increasingly recognised as one of the primary causes of obesity in western nations (6) .The impact of the environment on energy balance seems to be unidirectional; modern lifestyle promotes sedentary rather than physically active pursuits and thus positive rather than negative energy balance (7–9). Variations in the specific set of susceptibility genes of individuals determine the physiological impact of particular factors by which lifestyle and the environment influence energy balance (10) and subsequently individual susceptibility to obesity and the metabolic syndrome. Hill et al. (11) proposed that susceptibility to developing obesity could be due to metabolic susceptibility (e.g., tendency to store rather than burn excess body fat, differences in skeletal muscle composition), and/or to behavioral susceptibility (tendency to overeat or to be sedentary). The fact that obesity rates have been gradually increasing might also suggest that people with a high metabolic susceptibility are experiencing weight gain first as the environment becomes more obesigenic (i.e., increased food availability, high energy dense food supply, decreased need for physical activity).
How are exogenous–environmental inputs contributing to the regulation of energy homeostasis? It is important to recognize the existence of at least two inﬂ uential systems. First a central neural network stretching from the hypothalamus to the caudal medulla, responsive to leptin and other peripherally secreted signals conveying information on energy and metabolic status, has been identiﬁed as the homeostatic control system for the regulation of food intake and energy balance. This system acts as an integrative metabolic sensor generating output signals to control energy intake and expenditure in a coordinated fashion (see subsequent chapter on central regulation of energy homeostasis). While this system is remarkably powerful in defending the lower limits of adiposity, it is apparently very weak in curbing appetite in a world of afﬂ uence.
Alongside the above-mentioned homeostatic neural system operates another neural non-homeostatic, “hedonic” system that processes appetite, sensory inputs, and rewarding aspects of food intake, ultimately resulting in increased energy intake in genetically predisposed individuals. Food palatability may have an independent effect and/or interact with a number of neurotransmitter systems (including dopamine (12) , serotonin (13), and endorphins (12,14,15)) that contribute to appetite, reward, and mood regulation. Although it is not well understood how the reward value of pleasurable taste and ﬂ avor guides ingestive behavior, psychological components that translate reward into learning, liking, and wanting more food play a very important role in the pathogenesis of obesity and have been outlined in recent reports (16).
A further question is whether these systems operate independently of each other or whether they may interact. Recent ﬁnding suggest a role for nucleus accumbens– hypothalamic pathways in the interaction between the “cognitive” and “emotional” brain and the “metabolic” brain and thus between non-homeostatic and homeostatic factors that control food intake (17–21); however, more studies are clearly needed to elucidate these mechanisms.
The orosensory properties of food, mainly mediated by palatability, play a significant role in regulating eating. On a moment-to-moment basis, eating is controlled predominantly by the orosensory effects of food such as taste, flavor, aroma, and texture of food that provide positive feedback, and the postingestive effects that provide negative feedback. The effects of entry of palatable food in the mouth are stimulatory, while the entry of food into the stomach is inhibitory (22). Thus, heightened responsiveness to hedonic factors, including increased palatability, is often cited as a major factor in the development of obesity, but more needs to be learned in this field and this area is currently the focus of intensive research efforts (23).
Both appetite and food preferences are altered across a range of mood states; preference for “junk food” and increased caloric intake is enhanced during negative mood states whereas preference for health(Buy now from http://www.drugswell.com)ier foods is increased during positive mood states (24). Numerous associations between mood states and emotional eating have been reported (25), and stress-associated eating (i.e., emotional eating) is more common in those who are overweight or obese. Various psychological theories of emotional eating have been proposed (26,27), most of which conclude that emotional eating fails to produce any lasting benefit to psychological and mood states.
In summary, eating behavior links the internal world of molecules and physiological processes with the external world of physical and cultural systems. The extent to which human eating patterns are a function of physiological or environmental pressure is not always clear. Understanding the pathways responsible for the neural control of feeding and how the integration of diverse signaling systems could be translated into the expression of behavior and the accompanying subjective feelings is deemed to be important for the development of behavioral strategies and pharmacological therapies against obesity.
Development of obesity and type 2 diabetes could ensue from alteration in the balance in the nutrient-activated mechanisms/nutrient-sensing pathways (28). It has been proposed that circulating factors, e.g., lipids, glucose, or protein products, that are generated in proportion to body fat stores and/or nutritional status act as signals to the brain, eliciting changes in energy intake and expenditure (29). A prolonged period of excessive food intake has been proposed to lead to weight gain and insulin resistance by activating nutrient-sensing pathways which process the signal for the availability of nutrients at central sites (hypothalamus) as well as directly in peripheral tissues (muscle and fat). All these pathways may either act independently or converge to decrease expression of proliferator-activated receptor coactivator 1 (PGC-1) α and β, key coactivators of PPAR α, γ, and δ, leading to mitochondrial dysfunction and reduced energy expenditure, all of which enhance the risk for obesity and insulin resistance (30).
We will further discuss the role of fatty acid metabolism in regulation of energy homeostasis, since very recent modalities for treating obesity are based on this metabolic pathway. We will then review the role of dietary fat and dietary carbohydrates in regulating body weight, since diet, including low fat or low carbohydrate diets, still remain the most important therapeutic modality for weight loss.
4.1. The Role of Fatty Acid Metabolism in Regulation of Energy Homeostasis
A potential role in the regulation of energy balance for fatty acid metabolism acting in the brain or in the periphery has been considered only recently. Several studies indicate that inhibition of FAS, the enzyme that catalyzes the synthesis of long-chain fatty acids, using either cerulenin, a natural FAS inhibitor, or synthetic FAS inhibitors, reduces food intake and causes profound and reversible weight loss (31–38) . Through central, peripheral, or combined central and peripheral mechanisms, these compounds increase energy consumption to augment weight loss (39). Centrally, these compounds reduce the expression of orexigenic peptides (40). In vitro and in vivo studies indicate that, at least in part, C75’s effect is mediated by modulation of adenosine-monophosphate-activated protein kinase (AMPK), a member of an energy-sensing kinase family (41,42). These compounds, with chronic treatment, also alter gene expression peripherally to favor a state of enhanced energy consumption (36,37). While the question of the physiological role of fatty acid metabolism remains to be fully elucidated, these effects raise the possibility that pharmacological alterations targeting molecules important in fatty acid synthesis/degradation may prove to be useful targets for obesity therapeutics.
Dietary fat is the most energy-dense macronutrient in the diet (43). Short-term feeding studies have indicated that dietary fat might be used more efficiently than carbohydrates and thus it accumulates as body fat (44). When these short-term feeding studies are extended to 4 days, however, no difference in stored energy is observed (44,45) . It has thus been suggested that carbohydrate intake, unlike fat intake, is regulated (46). The rationale underlying the promotion of low-fat diets is largely based on the belief that dietary fat is positively associated with body fat through the high energy density of fat and enhanced palatability of high-fat foods (43). However, traditional recommendations of fat restriction have been shown to have a negligible effect on long-term weight loss
(43) whereas low-fat diets may also not offer any benefit in terms of reducing the risk of cardiovascular disease (47). Thus, further studies are needed to clarify the role of dietary fat in regulation of energy homeostasis.
4.3. The Role of Dietary Carbohydrates in Regulation of Energy Homeostasis
Recent studies indicate that low-carbohydrate diets might be more effective for short-term weight loss than low-fat diets, although this has not been verified by longer-term studies (48). Weight loss while following a low-carbohydrate diet is thought to result from a combination of factors: the satiating effect of protein (49), increased energy expenditure (50,51), appetite suppression from ketosis, as well as restriction of food choice (52–60). More research is needed to fully define the exact role of low carbohydrate diet in the long-term regulation of body weight, and to elucidate the underlying mechanisms.
Hormonal systems serve as peripheral signals to CNS to provide information regarding energy storage and metabolic state. These hormones deriving mainly from the adipose tissue, the gastrointestinal tract, and the pancreas contribute to the homeostatic control system for the regulation of food intake and energy balance.
Adipocytes are active endocrine cells that secrete numerous proteins and bioactive peptides known as adipokines, which act at both the local (paracrine/autocrine) and systemic (endocrine) level. The adipose tissue is therefore considered today as a true endocrine organ (see Table 1 and Fig. 1) (61). The most intensively studied and cur-
The Adipose Tissue as an Endocrine Organ: Molecules Secreted by Adipose Tissue
Hormones Leptin, adiponectin, resistin, estrogens, angiotensinogen, retinol binding protein 4, visfatin, apelin
Cytokines IL-6, TNF- α
Complement factors Adipsin (complement factor D), complement C3, complement factor B, ASP
Extracellular matrix proteins Type I, II, IV, VI collagen, ﬁ bronectin, osteonectin, laminin, entactin, matrix metalloproteinases 2 and 9
Other immune-related proteins MCP-1
Proteins of the RAS Renin, AGT, AT1, AT2, ACE
Acute phase response proteins α1-acid glycoprotein, haptoglobin
Proteins involved in the ﬁ brino-PAI-1, tissue factor lytic system
Enzymes and transporters LPL, CETP Apolipoprotein E, Adipocyte fatty acid involved in Lipid metabolism binding protein, CD36.
Enzymes and transporters Insulin receptor substrate 1,2, Phosphatidylinositol 3-kiinvolved in glucose metabolism nase, protein kinase B (Akt), GLUT4, protein kinase λ/ζ
Enzymes involved in steroid Cytochome-P450-dependent aromatase, 17βHSD, metabolism 11βHSD1
Receptors of peptides and Insulin, glucagon, thyroid-stimulating hormone, growth glycoproteins hormone, angiotensin-II, gastrin/cholecystokinin B, adiponectin
Receptors of cytokines IL-6, TNF- α , leptin
Nuclear receptors PPARγ, glucocorticoid, estrogen, progesterone, androgen, thyroid, vitamin D, nuclear factor-kB Other Prostacyclin, FFAs
Il-6 interleukin 6, TNF tumor necrosis factor, MCP-1 monocyte chemoatractant protein 1, ASP acylation stimulating protein, 11bHSD-1 11b-hydroxysteroid dehydrogenase type 1, 17bHSD 17b-hydroxysteroid dehydrogenase, LPL lipoprotein lipase, CETP cholesterol ester transfer protein, AGT angiotensinogen, AT1 and 2 angiotensin receptor type 1 and 2, ACE angiotensin-converting enzyme, PAI-1 plasminogen activator inhibitor, FFAs free fatty acids, PPAR γ peroxisome proliferator-activated receptor gamma
Fig. 1. Integration of environmental and peripheral signals by the central nervous system.
rently considered most important molecules secreted by the adipose tissue are leptin, adiponectin, and interleukin-6 (IL-6), which are discussed below.
Leptin, a 16-kDa protein, is the product of the ob (leptin) gene. Its discovery has changed the concept of white adipose tissue from that of an inert tissue to that of an active endocrine organ. Leptin is expressed predominantly in adipocytes (62) but has also been found in the hypothalamus, pituitary, placenta, skeletal muscle, and the gastrointestinal tract (63). Leptin circulates in the blood stream in a free and a bound form, and mediates its metabolic effects by binding to and activating the long isoform of a specific receptor known as ObRb (64). Signaling pathways downstream of leptin include the JAK STAT pathway, MAP kinase, and PI3 kinase (65). Leptin levels decrease in response to caloric restriction (66) and they increase in response to overfeeding irrespective of adipose tissue mass. Leptin secretion is also increased by insulin, glucocorticoids, tumor necrosis factor alpha, and estrogens, and is decreased in response to starvation (67), β3 -adrenergic activity (68), free fatty acids, growth hormone, androgens, and PPAR γ agonists, as reviewed in detail elsewhere (69).
The discovery of leptin not only led to the realization that leptin per se plays a pivotal role in the regulation of energy homeostasis but also opened the black box of energy homeostasis regulation. Leptin is thought to act as a lipostat: as the amount of fat stored in adipocytes rises, leptin is released into the blood and signals to the brain information on adequacy of energy stores. Recent studies in mice underline the important role of leptin in the development of hypothalamic circuits regulating energy homeostasis (70) since leptin may affect the synaptic plasticity of hypothalamic neurons (71) and may also act as a neurotrophic factor during hypothalamic development (72).
Although the role of leptin appears to be of signiﬁcance in both ends of the energy homeostasis spectrum, i.e., obesity and energy-deﬁcient states (73), our work has demonstrated that in humans leptin’s role appears to be of much more important in states of energy deprivation (74–76). Our group has also recently shown that falling leptin levels below a certain threshold can result in several neuroendocrine changes and immune abnormalities that occur with starvation (75,77) whereas no alterations of these neuroendocrine axes and immune response occur when leptin ﬂuctuates within the normal range (78). Importantly, extremely thin women with hypothalamic amenorrhea and/ or anorexia nervosa have low leptin levels (79,80), whereas exogenous leptin normalizes neuroendocrine and reproductive function in women with relative hypoleptinemia (76). The role of leptin in human obesity is intriguing. In rodents diet-induced obesity has been correlated with the development of leptin resistance (81,82). Mutations in ob gene (leptin gene), as well as the leptin receptor gene, result in morbid obesity and diabetes in rodents and humans (62,83–85); however, these cases are extremely rare. The majority of obese individuals are characterized by high levels of leptin (86) , suggesting leptin insensitivity or resistance; in fact, leptin administration to obese subjects has only a moderate effect on body weight (87). Importantly, negative regulators of both leptin and insulin signal transduction, such as inhibitors of protein tyrosine phosphatase 1B, may provide opportunities for the treatment of both obesity and insulin resistance by improving these hormone resistance syndromes (69,88). Finally, the prospect that leptin administration in replacement doses might prove clinically useful to maintain weight loss and the resulting relative hypoleptinemia that has been achieved by more traditional means (89,90) is an exciting possibility. Further testing of this concept in humans is the focus of many research efforts. The complex role of leptin in regulation of energy homeostasis and neuroendocrine function is summarized in Figs. 2 and 3a and in Tables 2 and 3 .
Adiponectin, a 247-amino-acid protein produced exclusively by adipocytes, circulates in trimers and higher order oligomers (91–94) (Figs. 3b and 4 ). Different adiponectin isoforms, bind and activate at least two adiponectin receptors, which in turn alter the phosphorylation state of 5¢-AMP kinase and possibly other downstream molecules (94,95). Adiponectin receptor 1 (AdipoR1), which is expressed ubiquitously, but most abundantly in skeletal muscle, has a high affinity for globular adiponectin and a very low affinity for full-length adiponectin, whereas adiponectin receptor 2 (AdipoR2), which is found predominantly in the liver, has an intermediate affinity for both forms (96).
Adiponectin is currently considered to regulate not only insulin resistance but also possibly energy homeostasis (91). It decreases with increasing overall and central adiposity (92,97–99), and increases with long-term weight reduction (100) . Adiponectin is increased after food restriction in rodents (101). Its levels are regulated in rodents by ageing and high fat diet (102), and in humans by certain genetic polymorphisms (103), Mediterranean diet (104), glycemic load (105), and exercise (106). Studies in rodents have revealed that peripheral adiponectin administration reduces body weight and visceral adiposity without affecting food intake (107,108), increases insulin sensitivity, and decreases lipid levels in rodents (109–111). These effects are proposed to occur mainly by regulating energy expenditure, increasing glucose uptake, free fatty
Fig. 2. Leptin’s role in energy homeostasis and neuroendocrine regulation. States of energy excess are associated with increased leptin levels but both neuroendocrine function and energy homeostasis are resistant to the effects of increased leptin. Energy deﬁciency results in decreasing leptin levels and reduced leptin receptor activation in the arcuate nucleus of the hypothalamus. This leads to activation of a complex neural circuitry comprising orexigenic and anorexigenic signals. The main anorexigenic peptides are proopiomelanocortin and cocaine and amphetamine regulated transcript; these are stimulated by leptin. The main orexigenic peptides downstream of leptin are neuropeptide Y and agouti-related protein; both potently stimulate food intake and reduce energy expenditure, thereby promoting weight gain in response to reducing leptin levels. In the ﬁgure the response to anorexigenic stimuli (activated in states of energy excess) is shown. “+” indicates stimulatory effects; “−” inhibitory effects. In states of energy deﬁciency the exact reverse pathways are activated.
acid oxidation, and oxygen consumption in the periphery (95,108,109). This effect on energy expenditure appears to be mediated by the hypothalamic melanocortin system (111). Adiponectin knockout mice have severe diet-induced insulin resistance (112). Importantly, accumulating evidence indicates that the primary role for adiponectin is to regulate insulin sensitivity (96,110,113–115).
Circulating adiponectin levels correlate negatively with insulin resistance (98) , and low adiponectin levels predict increased risk for developing insulin resistance, diabetes, cardiovascular disease and may represent a link between obesity and certain malignancies (116). On the other hand, adiponectin levels are higher in states of improved insulin sensitivity, such as after weight reduction or treatment with insulin-sensitizing drugs,
e.g. thiazolidinediones (94). In addition to its insulin-sensitizing effects, adiponectin can decrease lipid levels (111) and has potent anti-inﬂ ammatory (117) and atheroprotective effects (118–120). Although metabolic pathways that are involved in regulation of food intake, gluconeogenesis, and lipogenesis (121) mediate some of the actions of adiponectin,
Actions of Leptin That Can Regulate Energy Homeostasis and Metabolism by Organ and System
Action of leptin Type of action of leptin
Energy intake Binding to and activation of leptin receptors found in hypothalamic nuclei (mainly, but not exclusively, in arcuate and paraventricular nucleus of the hypothalamus) and brainstem, triggers circuits inhibiting appetite (mainly through upregulation of α-MSH (POMC)) and inhibits circuits stimulating appetite (mainly by suppressing neuropeptide Y and agouti-related peptide (AgRP) expression in hypothalamic nuclei) (300).
Energy expenditure Experimental evidence points to both acute and chronic effects of leptin to increase energy expenditure, both via activation of BAT and increases in SNS ﬁring per se (301,302) . Acute effects of leptin include increased catecholamine turnover in BAT (301), increased SNS ﬁring in numerous thermogenic tissues (302), and lipolysis (303). The acute effects of leptin may be important for body weight regulation because leptin may prevent the decrease in energy expenditure that normally accompanies decreased food intake in mice (304) and humans (89). Leptin administration has not been shown to alter SNS activity in health(Buy now from http://www.drugswell.com)y humans in the short term (305) but may alter SNS activity in long-term weight-loss-induced hypoleptinemia in humans (89). In any case, leptin’s effect on energy expenditure in both weight-loss-induced and congenital hypoleptinemia appears to be relatively small (85).
Autonomic nervous Activation of leptin receptors in the ventromedial hypothalamus
system axis and arcuate nucleus results in modulation of autonomic nervous system activity. Acute leptin injections (i.v., intracerebroventricular – ICV, or intrahypothalamic into the VMH) increase sympathetic nerve activity in mice (306–308). Through activation of sympathetic nerves, leptin stimulates free fatty acid oxidation and thermogenesis in brown adipose tissue in rodents (309) . No similar effects have been demonstrated to date in humans (305).
Peripheral tissues Leptin increases glucose uptake in several tissues, including muscle and brown adipose tissue, and thus seems to play a role in modulating peripheral insulin sensitivity (310). The latter is likely to also involve activation of central melanocortin neurons but more research is needed for underlying mechanisms to be fully elucidated. Leptin administration has been shown to improve insulin resistance in humans with congenital (311) or relative acquired leptin deﬁ ciency (310). Other important actions of leptin include regulation of immune function, hematopoiesis in mice (312) and humans (313,314), angiogenesis (73) and ﬁ nally bone metabolism (73).
BAT brown adipose tissue, MSH a -melanocyte-stimulating hormone, POMC proopiomelanocortin, SNS sympathetic nervous system
The Role of Leptin in Energy Homeostasis
The role of leptin in states of energy excess
The role of leptin in states of energy deﬁ ciency
a Leptin b Adiponectin
Fig. 3. Tertiary structure of leptin ( a) and adiponectin (b ).
Non-homologous Collagen-like Region Domain Globular Domain
MMW (Hexamer) LMW (Trimer)
Fig. 4. (a) Primary structure of adiponectin. (b) Multimeric structure of adiponectin. (c ) Multimers of adiponectin in an SDS gel (Western blot). HMW high molecular weight, MMW middle molecular weight, LMW low molecular weight adiponectin.
the mechanism by which this adipokine improves insulin resistance, glucose metabolism, and attenuation of weight gain remains to be fully elucidated. Further studies are needed to fully elucidate the role of adiponectin in regulation of energy homeostasis.
IL-6 is a multifunctional immune-modulating cytokine that circulates at high levels in the blood stream. It has been suggested to have important functions in glucose and lipid metabolism. IL-6 is secreted from adipose tissue into the circulation, and its expression is positively correlated with BMI and total fat tissue mass. IL-6-knockout mice develop obesity, which can partly be reversed by IL-6 replacement, suggesting a role for IL-6 in the long-term regulation of adipose tissue mass (122). Furthermore, central administration of a low dose of IL-6 decreases feeding and increases energy expenditure in rats, suggesting a central site of action for IL-6 (122). Importantly, obesity can be associated with relative deficiency of IL-6 centrally, since IL-6 levels in the CNS correlate inversely with subcutaneous and total body fat in overweight and obese humans (123). Serum levels and tissue expression of IL-6 decrease in response to diet-induced weight loss and increase with increasing adiposity (124). Increased production of IL-6 by the adipose tissue, especially visceral adipose tissue (125), of obese subjects may represent a compensatory mechanism attempting to limit obesity. Plasma concentrations of IL-6 can predict the development of type 2 diabetes and cardiovascular disease (61) since increased IL-6 levels result in a proinflammatory state, as well as insulin signaling defects and thus insulin resistance (125,126).
Other interleukins, including IL-18 and IL-1, are also involved in body-weight homeostasis. IL-1 type I receptor knockout mice display an obese and insulin-resistant phenotype. This obese phenotype is characterised by a decrease in leptin sensitivity, fat utilization, and locomotor activity (127). The emerging role of interleukins in energy homeostasis and insulin resistance has been recently reviewed extensively elsewhere.
Resistin, a recently identified 114-amino-acid protein, is almost exclusively expressed in white-adipose tissue. Its concentrations have been reported to be higher in insulin-resistant states as well as in visceral vs. subcutaneous adipose tissue (128) . Circulating resistin is increased in obese rodents (128) and humans (129) and falls after weight loss in humans (130). Whether resistin influences obesity or insulin resistance either directly or by altering glucose and insulin levels and/or whether resistin may play a direct or indirect role in inflammation associated with obesity (131) warrants further investigation. Studies have shown contradictory results (128,132–139). Further studies are clearly needed to elucidate the role of resistin in regulation of energy homeostasis (140).
Apelin, a hormone with considerable sequence similarity with the angiotensin receptor type 1 (AT-1) gene, was discovered many years ago (141) but its production in adipose tissue and its potential modulating effect on obesity were recognized only very recently (142). Apelin, similar to leptin and insulin, is an adipocyte-generated signal circulating in proportion to body fat stores that may be acting to reduce food intake. In addition, similar to leptin, upregulation of apelin gene expression has been observed in certain mouse models of obesity while insulin regulates apelin expression in adipose tissue (142,143). Thus except for the previously described beneficial effects of apelin on cardiovascular physiology and insulin sensitivity (143), apelin may also play a protective role in obesity-associated disease states. However, more experimental evidence on the proposed roles of apelin is needed since available data remain controversial (142,144–146).
Pre-B-cell colony-enhancing factor, a growth factor for early B lymphocytes previously known to be synthesized in bone marrow, liver, and skeletal muscle, was recently found to be highly expressed in human visceral fat (147,148) and was referred to as “visfatin” since plasma visfatin concentration was found to correlate strongly with the amount of visceral fat (147). Plasma visfatin levels were found to be almost twofold higher in mice made obese by a high-fat diet in comparison to lean animals (147). In humans, plasma visfatin has also been reported to correlate significantly with visfatin mRNA level in visceral adipose tissue, percent body fat, and body mass index (148). Experimental data also suggest that endogenous visfatin is involved in the regulation of glucose homeostasis (147) and plasma visfatin levels are also higher in patients with type 2 diabetes mellitus than in normoglycemic controls (149,150), although this has not been confirmed by all studies (151) . Future studies are needed to clearly establish the exact role of visfatin in the development of obesity and diabetes.
Adipocytes produce other cytokines also, including tumor necrosis factor alpha (152) and proteins such as macrophages and monocyte chemoatractant protein 1, plasminogen activator inhibitor 1, and acylation stimulating protein (ASP), all of which have also been studied in the context of regulation of obesity, metabolism, and the insulin resistance syndrome (61). These and other adipocyte-secreted molecules (see Table 1 ) are the focus of intensive research efforts and their study is expected to contribute significantly to our understanding of the mechanisms regulating nutrition, metabolism, and energy homeostasis.
Insulin, a 51-amino-acid hormone, appears to be one of the most important hormones regulating energy homeostasis. It is secreted from pancreatic beta cells and acts by binding to and activating a glycoprotein insulin receptor expressed on the plasma membrane of almost all cells. Subsequent tyrosine phosphorylation of the insulin receptor and initiation of intracellular signaling lead to regulation of key cellular activities, including gene expression, glucose uptake and oxidation, and synthesis of glycogen, triglycerides, and protein (153).
Key areas responsible for controlling food intake, such as the arcuate nucleus in the hypothalamus, express insulin binding sites (154), and intracerebroventricular infusion of insulin dramatically decreases food intake and body weight in animals (155) . In contrast, neuron-speciﬁc insulin receptor knockout mice demonstrate increased food intake, body weight, and adiposity, suggesting that insulin, similar to leptin, plays a key role in regulating energy balance (156,157). Animal models of diet-induced obesity and leptin resistance are also characterized by insulin resistance and reduced insulin transport into the brain and thus weight gain and increased food intake may be due to decreased central insulin levels in addition to defective leptin transport and leptin resistance (158). Although both the melanocortin and neuropeptide Y (NPY) systems are important downstream mediators of insulin’s actions on food intake and body weight, the pathways mediating insulin’s effects on food intake remain to be fully elucidated (159–161).
In humans, insulin, similar to leptin, circulates in levels proportional to the degree of adiposity (162) which may serve to overcome impaired insulin-mediated intracellular signaling or to increase insulin levels centrally (153). Negative regulators of both leptin and insulin signal transduction, such as inhibitors of protein tyrosine phosphatase 1B, may provide opportunities for the treatment of both obesity and insulin resistance (88). Several compounds are currently in preclinical development by several pharmaceutical companies and are anticipated with great interest as potential new treatment options for obesity and diabetes.
Pancreatic polypeptide (PP) is primarily produced by cells of the islets of Langerhans (163). It may modulate expression of other gut hormones such as ghrelin (164) and/or regulate other hypothalamic neuropeptides such as NPY and orexin (164) and convey anorectic signals via brain stem pathways (165). Thus even though PP could be unable to cross the blood–brain barrier, it is possible that it could still regulate appetite. Although less data are available on the interaction between PP and other adipokines such as leptin, it has been shown that PP administration in leptin-deficient ob/ob mice decreases body weight (164). We did not find any leptin-induced alterations in PP levels in a recent interventional study in humans (166).
Transgenic mice overexpressing PP are leaner than controls (167), and chronic peripheral administration of PP to mice reduces body weight (168). The actions of PP on food intake seem to depend on the route of administration. In obese rodents, peripheral PP administration decreases food intake, reduces energy expenditure and body weight, and improves insulin resistance and dyslipidemia (164,169). In humans, PP may reduce food intake in normal-weight human volunteers (170) and in patients with Prader–Willi syndrome (171). In contrast to the peripheral actions of PP, central administration of PP into the third ventricle increases food intake (172) but the mechanisms involved remain to be fully elucidated. Plasma PP concentrations have been inversely associated with adiposity and subjects with anorexia have elevated levels of this peptide (173,174) , while reduced levels of plasma PP (175,176) have been linked to hyperphagia and obesity in obese subjects (177,178). However, other studies show no difference in plasma PP concentrations in response to weight loss in obese subjects (179), or between lean and obese subjects (180), with the exception of Prader–Willi syndrome. Although observational studies of PP levels in humans are conﬂ icting (176,181), intravenous infusion of PP in normal-weight subjects has been shown to reduce 24-h energy intake (170). Longitudinal prospective evaluation of Pima Indians over 5 years indicate that PP’s role in regulating energy balance may be complex, since higher fasting PP levels were associated with greater risk of weight gain, but higher postprandial PP levels were associated with decreased risk of weight gain (182). Thus, the efﬁ cacy of PP infusion in obesity remains to be further studied.
Amylin, produced by the beta cells of the pancreas, is secreted along with insulin in response to food ingestion. Its best known functions are to reduce food intake and gastric emptying, and to inhibit pancreatic glucagon secretion and pancreatic and gastric enzyme secretion (183). Importantly, amylin is deficient in patients with type 1 diabetes, who are also deficient in insulin (183). In rats, amylin decreases food intake, body weight, and fat mass, while inhibition of amylin signaling has the opposite effect (184,185).
Finally, there is evidence that amylin functions as an adiposity signal controlling body weight (183,186), but the magnitude of its effects appears to be relatively small. Amylin may interact with other signals controlling energy homeostasis at the level of the hypothalamus and probably elsewhere, enhances the action of other satiety signals at the level of the hindbrain, and can lead to reduction of meal size (185,187,188) . In rats, amylin has a synergistic effect with leptin to induce weight loss (189) , speciﬁ cally decreasing fat mass (190), and a recent clinical trial in humans involving administration of amylin and leptin suggests a similar synergy ( http://www.amylin.com ). Using an interventional study design in health(Buy now from http://www.drugswell.com)y normal-weight humans, we have recently demonstrated that amylin levels are decreased during short-term complete fasting, but this effect is not mediated by leptin; we have also shown that amylin levels are not altered by chronic energy deﬁcit or normalizing leptin levels for up to 3 months (166) . Thus, any potential synergistic effect of amylin and leptin to mediate weight loss is likely not due to alterations of amylin levels by leptin, but may be related to central mechanisms and/or synergies in enhancing intracellular signaling.
The synthetic amylin analog pramlintide is marketed for diabetes treatment, but its administration for at least 16 weeks in humans also causes mild progressive weight loss (191,192) and can induce weight loss in individuals with (193) and without diabetes (194). More studies are needed to fully quantitate amylin’s weight reducing capacity, its potential synergistic effects with other peptides, and to carefully study potential side effects.
The gastrointestinal tract is also an endocrine organ and an important source of peptide hormones which regulate energy balance. Gastrointestinal hormones have been proposed to contribute to short-term regulation of energy homeostasis in contrast to adipose-tissue-secreted or pancreas-derived hormones which have been proposed to provide long-term signals that regulate energy homeostasis,. Therefore, gut hormone signaling systems represent important pharmaceutical targets for potential antiobesity therapies that would have a short acting role. Of the several gastrointestinal-tract-generated molecules we will focus herein on those considered to be the most important, such as ghrelin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and oxyntomodulin, cholecystokinin (CCK), and bombesin-like peptides.
Ghrelin, a 28-amino-acid peptide, is mainly expressed in enterochromaffin cells of the stomach fundus (195) but may also be expressed centrally in the hypothalamus (196). Its action is thought to be mediated via the growth hormone secretagogue receptor (GHS-R) type 1a expressed in numerous tissues, including hypothalamus, pituitary, liver, and the gastrointestinal tract (195). Plasma ghrelin levels are regulated both by food intake and by endogenous diurnal rhythms (197). In normal humans, ghrelin levels rise before meals
(197) and in response to diet-induced weight loss (198) whereas they fall acutely after feeding. The rise in preprandial ghrelin correlates with hunger scores in human subjects eating spontaneously (199). Interestingly, the levels of ghrelin are correlated with adiposity in humans, with an inverse relationship between plasma ghrelin levels and BMI (200). Obese human subjects show reduced levels of plasma ghrelin, which rise to normal after diet-induced weight loss (198). Moreover, in obese individuals the postprandial regulation of ghrelin seems to be altered, which may be related to continuous food intake and/ or obesity (201). Obese patients have also decreased ghrelin levels after gastric bypass surgery, which may contribute to maintaining decreased weight after surgery (198). Furthermore, recent data in humans have demonstrated an inverse correlation between ghrelin and leptin, but we have shown no direct regulation of ghrelin by leptin administration over the short term (period of a few hours to a few days) (202). Peripheral and central administration of ghrelin to rodents induces positive energy balance by decreasing feeding, as well as fat mass, and reduces fat utilization (203,204). Ghrelin is unique because it is the only known gut hormone stimulating food intake. Intravenous administration of ghrelin to health(Buy now from http://www.drugswell.com)y volunteers increases food intake (205).
A potentially important application of ghrelin is that ghrelin antagonists could possibly be developed as antiobesity drugs. It has been shown that GHS-R knockout mice are resistant to diet-induced obesity (206,207) and favor fat as a metabolic substrate when on a high-fat diet (208). In another study, ghrelin and GHS-R knockout mice were found not to have profoundly altered food intake or body weight on a normal diet (209,210). GHS-R antagonists may therefore have beneﬁcial effects in obese humans on high-fat diet, but more experiments are needed to establish this hypothesis.
Knockout models have also provided further evidence for the role of ghrelin in glucose homeostasis. Diabetic ghrelin knockout mice show less dramatic hyperphagia than do controls (211), and ablating ghrelin attenuates diabetes in the ob/ob mouse models of obesity (212). Moreover, ghrelin administration has been demonstrated to increase food intake in certain patient groups such as in cancer (213) and dialysis patients (214) and thus reduced ghrelin levels may be responsible in part for the loss of appetite and weight often observed in these patients (213,214). Whether ghrelin plays an important role in regulating energy homeostasis in humans remains to be seen through future interventional studies involving new ghrelin analogs and antagonists currently in development by pharmaceutical companies.
PYY, a 36-amino-acid peptide (215), is secreted from the L cells of the small and large bowel (216). There are two main forms of PYY in the circulation: PYY1–36 and PYY3– 36 (217). PYY levels decrease with fasting and increase rapidly after a meal (218) . PYY inhibits food intake through a gut–hypothalamic pathway that involves inhibition of NPY via Y2 receptors in the arcuate nucleus and the dorsal motor nucleus of the vagus nerve (219). Peripheral administration of PYY delays gastric emptying and gastric secretion, inhibits food intake, and reduces weight gain in animals and humans (220–225) . However, centrally administered PYY increases food intake in rodents (226,227). In humans, endogenous levels of PYY may be lower in obese subjects, and PYY reduces appetite and food intake when administered to obese or normal-weight subjects, suggesting that a relative PYY deficiency may contribute to the development of obesity (228) . We have shown in humans that PYY increases after meal ingestion and decreases after fasting in a manner consistent with a meal-related signal of energy homeostasis but circulating levels of this gut-secreted molecule are independent of regulation by leptin over the short term (229).We have also recently found that PYY levels are higher in obese patients after gastric bypass surgery, a fact that may contribute to the increased efficiency of this procedure in decreasing body weight (230). In a short phase Ic trial of 37 obese participants a PYY nasal spray yielded somewhat promising results causing 1.3 lb of weight loss in 6 days whereas an injectable PYY analog (AC-162352) has been tested in phase I studies, with limited success due to nausea (231). Ongoing clinical trials involving PYY administration are awaited with great anticipation to further elucidate the role of this peptide in the treatment of obesity in humans.
Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptides (mostly GLP-1 but also GLP-2) are intestinal hormones that are released in response to ingestion of nutrients, especially carbohydrate (232) . They have a number of important biological effects, which include release of insulin, inhibition of postprandial glucagon release, maintenance of β-cell mass, delay of gastric emptying, and inhibition of feeding which result in negative energy balance (232) . These properties allow them to be potentially suitable agents for the treatment of type 2 diabetes.
Exogenous GLP-1 (central or peripheral administration) has been found to reduce food and caloric intake (233,234), and to decrease weight gain (235), body weight, and adiposity in rodents, whereas immunoblockade of central GLP-1 with antibodies results in increased energy intake (236,237). Moreover, mice deﬁcient in dipeptidyl peptidase IV (DPP-IV), an inhibitor of GLP-1 degradation, are resistant to diet-induced obesity and insulin resistance. Regardless of the anorectic actions of GLP-1 reported in rodents, GLP-1 receptor knockout mice have normal feeding behavior (238,239). The anorectic effect of GLP-1 is also present in humans (240,241). Preprandial subcutaneous GLP-1 injections reduce caloric intake by 15% and result in 0.5 kg of weight loss over 5 days in obese individuals (242). Therefore, low circulating GLP-1 could likely contribute to the pathogenesis and maintenance of obesity, and GLP-1 replacement could restore satiety. The actions of both GLP-1 on feeding may be mediated via the GLP-1 receptor, which is expressed in the hypothalamus, brainstem, and periphery (243). Although GLP-1 is presumed to produce its anorectic effect by acting centrally, the exact mechanism of its action and its potential efﬁcacy in humans need to be further studied (232).
The role of GLP-2 has not been fully established; however, central administration reduces feeding, probably via GLP-1 receptor (244). No effect of GLP-2 on feeding has been reported in man (245).
GIP, a peptide secreted by the duodenum upon absorption of fat or glucose, is a potent insulin secretagogue (246). It has been suggested that GIP may be implicated in a peripheral decrease of energy expenditure and fat oxidation and is oversecreted in the diet-induced mouse model of obesity. GIP receptor knockout mice are protected from obesity and insulin resistance (246), but the role of GIP in humans is currently thought to be less important than that of GLP-1.
In clinical trials, incretin mimetics and GLP-1 agonists such as exenatide and liraglutide reduced fasting and postprandial glucose concentrations, with improvements in HbA1c and modest weight loss when added to existing metformin and/or sulfonylurea therapy in patients with type 2 diabetes (247–250). The modest weight loss caused by incretin mimetics underlines the important role of incretins in regulation of body weight and energy homeostasis. However, side effects, including nausea and vomiting, limit the development of stronger, more efﬁcacious, incretins that could lead to new potential medications for treatment of obesity. Another important category of agents that target the incretin axis include DPP-IV inhibitors, which act by suppressing the degradation of a variety of bioactive peptides, including GLP-1, thereby extending their duration of action (251). Sitagliptin was recently approved for the treatment of type 2 diabetes whereas vildagliptin is furthest along in late-stage clinical development among other DPP-IV inhibitors (251,252) . Signiﬁcant improvement of glycemic control in patients with type 2 diabetes has been observed with sitagliptin (253–256) and vildagliptin (257–259) treatment in several clinical trials. Long-term clinical studies are needed to determine the beneﬁts of targeting the incretin axis (alone or in combination with other medications) for the treatment of type 2 diabetes.
Oxyntomodulin (OXM) is released from the small intestine in proportion to caloric intake (260). Both central and peripheral OXM administration acutely reduces food intake in rodents (261,262), and repeated administration reduces body weight gain and adiposity (262) possibly through an effect on the thyroid axis and via increased energy expenditure (262). Studies in humans (263) have shown that OXM reduces hunger and food intake (263,264) and may also result in increased energy expenditure (265) . Long-term trials are needed to establish OXM as an antiobesity drug and whether it may be the first therapy to suppress appetite and to concurrently increase spontaneous activity.
CCK is a peptide that is released by the duodenum and jejunum in response to nutrient ingestion (protein and fatty acid) (266), and by acting via specific receptors, it slows gastric emptying and stimulates gastric distension, intestinal motility, gall bladder contraction, and pancreatic enzyme secretion (267,268). Antagonists of these receptors increase food and energy intake in rodents (269) and in human subjects (270).
Although peripheral administration of CCK reduces food intake acutely in animals and humans (267), it may also lead to a compensatory increase in daily meal number and thus results in little weight loss. Thus, despite its anorectic actions, repeated administration of CCK does not inﬂuence body weight, and CCK is mostly involved in the short-term control of food intake (271). Chronic administration of CCK antagonists or anti-CCK antibodies increases weight gain in rodents, but without a signiﬁcant change in food intake (272,273). The long-term effect of CCK on body weight may be the result of interaction with other signals of adiposity such as leptin, which enhances the satiating effect of CCK (274). The evidence for a role of CCK in long-term body weight regulation, and hence as a potential therapy for obesity, remains to be fully elucidated.
Bombesin and bombesin-like peptides such as gastrin-releasing peptide and neuromedin B are released from the gastrointestinal tract in response to food intake. These peptides result in decreased food intake (275) and duration of feeding (276,277) and act through specific G-protein-coupled receptors (278) which are widely expressed both in the gastrointestinal tract and centrally (275,279) and signal to the brain information on energy intake. Peripheral or central injections of bombesin reduce food intake (280,281) independently of CCK in rodents (282). Bombesin receptor 3 (BRS-3) knockout mice display hyperphagia, mild obesity, diabetes, and hypertension (283) New compounds targeting this pathway are currently under preclinical development and are expected to soon shed light on the role of these molecules in humans.
Apolipoprotein (apo) A-IV is a circulating glycoprotein secreted by the small intestine in humans. It has been considered a key peptide involved in the processing of ingested fat by the body (284). One site of action of the anorexic effect of apo A-IV appears to be within the brain since apo A-IV is synthesized in the ventrobasal hypothalamus (285) , a general area in which other important feeding-related neuropeptides are also produced, and hypothalamic apo A-IV mRNA levels fluctuate with metabolic state as well as with time of day (286–288). Apo A-IV is also present in the cerebrospinal fluid, and its cerebrospinal levels increase when fat is absorbed (289). Moreover, administration of exogenous apo A-IV in the third ventricle reduces food intake (290). Because both intestinal and hypothalamic apo A-IV are regulated by absorption of lipids, but not carbohydrates, this peptide may be an important link between short- and long-term regulation of body fat (286–288). A possible signaling role of apo A-IV in energy homeostasis is suggested by the fact that systemic administration of exogenous apo A-IV decreases dose dependently food intake of rats (286–289) and that administration of apo A-IV antiserum increases food intake and body weight (290). All of these findings suggest that apo A-IV likely interacts with other signals involved in the regulation of energy homeostasis, but more studies are clearly needed to fully elucidate its role.
Enterostatin is the aminoterminal pentapeptide of procolipase and is released from pancreatic procolipase by proteolytic activity in the small intestine after the ingestion of dietary fat (291). Enterostatin is expressed in both the gastrointestinal tract and the CNS since both procolipase and enterostatin have been localized to the gastric mucosa and to certain brain regions (amygdala, hypothalamus, cortex) (292). Enterostatin when administrated centrally or peripherally to overnight fasted rats induces satiation since it suppresses intake of a high-fat diet, but not a high-carbohydrate diet (293,294). Finally, a role for endogenously produced enterostatin in feeding behavior is suggested by its ability to increase intake of high-fat diets by the enterostatin antagonist β-casomorphin1–7 (295). Further studies are needed to fully elucidate the role of this peptide in regulation of food intake and energy homeostasis.
It has recently been reported that obestatin, a new peptide derived from the ghrelin gene, inhibits food intake by acting through the orphan receptor GPR39 (296,297). Despite this evidence there are some discrepancies in relation to the anorectic effect of obestatin (298) as well as its binding to GPR39 (299). If the anorectic effect is confirmed, this finding could provide a new drug target for the treatment of obesity.
In summary, regulation of energy homeostasis is extremely complex. Signals from the environment and the periphery are integrated by the CNS to regulate both energy intake and energy expenditure. As the secrets of the systems responsible for the energy homeostasis regulation continue to be decoded, promising prospects emerge for the development of novel antiobesity medications which should produce more substantial weight loss than is currently achieved with nonsurgical interventions. This will hopefully provide in the not so distant future substantial benefits to the increasing percentage of the population striving to control their body weight.
11 . Hill J, Pagliassotti M, Peters J. Nongenetic determinants of obesity and fat topography . In: Bouchard C, editor. Genetic determinants of obesity. Boca Raton , FL: CRC , 1994: 35–48.
– emerging clinical applications . Nat Clin Pract Endocrinol Metab 2006; 2(6):318–327.
183 . Lutz TA. Amylinergic control of food intake. Physiol Behav 2006.
211 . Dong J, Peeters TL, De Smet B, Moechars D, Delporte C, Vanden Berghe P et al . Role of endogenous ghrelin in the hyperphagia of mice with streptozotocin-induced diabetes . Endocrinology 2006 ; 147(6):2634–2642.
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_4, © Humana Press, a part of Springer Science + Business Media, LLC 2009
Key Words: Obesity , Energy homeostasis , Energy expenditure , Signals
Discovery of the fat hormone leptin as part of an “adipostatic” endocrine system of body weight regulation has elucidated our understanding of body weight homeostasis
(1) and has increased our knowledge of how peripheral endocrine organs and the central nervous system (CNS) interact in the control of energy homeostasis. Peripherally generated signals are integrated in the brain in a complex manner, resulting in activation of both anorexigenic and orexigenic pathways to regulate energy balance. The molecular elucidation of this complex system has improved our understanding of energy homeostasis.
Peripheral signals such as nutrients (mainly lipids and carbohydrates) participate in the regulation of energy homeostasis by activation of intracellular second messenger pathways through surface enzymes (2) and ion channels (3,4) expressed in hypothalamic neurons. In addition, the short-term regulation of feeding is accomplished by conduction of information from chemoreceptors (mainly CCK) or stretch receptors to brainstem through neural afferent signals from the periphery, conveyed mainly via the vagus nerve, which innervates densely the gastrointestinal tract (Fig. 1 ). All these peripheral signals are integrated in the CNS through complex neural structures, which are described below.
The hypothalamus plays a central role in the integration of peripheral signals in the current energy homeostasis model (2). Within the hypothalamus, the arcuate nucleus (ARC) is a major site of peripheral signal integration, as it is considered to be the key sensor of peripheral energy input (reviewed in (3)).
Peripheral signals act mainly on two distinct neuronal populations. One population coexpresses the orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY); the other population releases cocaine- and amphetamine-regulated transcript and pro-opiomelanocortin, both of which inhibit feeding (Fig. 1 ). Both of these populations project to the paraventricular nucleus (PVN) and other nuclei involved in energy regulation (4,5).
In states of positive energy balance, neurochemical signaling inhibits orexigenic centers and activates anorexigenic centers, while during negative energy states the opposite occurs. Energy-modulating neuropeptides as well as receptors for peripheral hormones, including leptin and insulin, as well as several sensors of nutrient intake and expenditure have been identiﬁed in brain stem neurons (3). Therefore, the brain stem appears to also play an important role in the integration of signals of energy availability (6) . Obviously, the energy homeostasis circuit is controlled at several levels and not only in the CNS.
Most individuals maintain stable body weight over long periods of time despite wide daily variations of food intake and energy expenditure (EE). For this to happen, food intake and EE must be constantly adjusted and precisely balanced over time. Currently, the emphasis in the regulation of body weight and endocrine function is placed on neuronal circuits, composed of specific neuropeptides, rather than specific hypothalamic nuclei that have been thought to play a major role in the past (see Fig. 1 ).
Fig. 1. Integration of peripheral signals in the hypothalamus and the central nervous system. The interaction between the various components of this complex system is noted, as are the neuropeptides that are expressed in each part of this complex circuit. ARC arcuate nucleus, AVP vasopressin, AgRP agouti related protein, CART cocaine- and amphetamine-regulated transcript, CCK cholecystokinin, CRH corticotropin releasing hormone, DMN dorsomedial nucleus, DRN dorsal reticular nucleus, GABA g-aminobutyric acid, GLP-1/2 glucagon-like peptide 1/2, IL-6 interleukin-6, LHA lateral hypothalamus, LPB lateral parabrachial nucleus, NA noradrenalin, NTS nucleus of the solitary tract, OXY oxytocin, PVN paraventricular nucleus, PP pancreatic polypeptide, POMC pro-opiomelanocortin, TNF-atumor necrosis factor alpha, TRH thyrotropin-releasing hormone, VMN ventromedial nucleus. + indicates orexigenic effect; −, anorexigenic effect; ?, unknown effect.
The arcuate nucleus (ARC), one of the hypothalamic nuclei, is thought to play a pivotal role in the integration of signals regulating appetite. This is because the immediate surroundings of the ARC are not being shielded by the blood–brain barrier and this allows unrestricted access to afferent inputs (8).
Neuropeptide Y and pro-opiomelanocortin neurons in the hypothalamic ARC are prototypic metabolic sensors. Both use glucose as a signaling molecule, and both have receptors for peripheral hormones, including insulin and leptin (8). The pro-opiomelanocortin neurons producea-melanocyte-stimulating hormone whose release and binding to melanocortin-3 and -4 receptors in the PVN and lateral hypothalamus reduces food intake and increases EE mainly through projections from these nuclei to autonomic and neuroendocrine effector systems (9). Firing of NPY neurons releases both NPY and AgRP; NPY (10) is an anabolic peptide that strongly stimulates ingestive behaviors and minimizes EE, whereas AgRP acts as a functional antagonist of catabolic melanocortin receptors. Under homeostatic conditions, leptin and insulin levels reﬂect the amount of adiposity in the body(7,11). In addition to input from insulin and leptin, the ARC also senses changes in energy balance conveyed by the gastric/gastrointestinal-system-secreted hormone ghrelin
(12) and the intestinal hormone peptide YY 3–36 (PYY 3–36) (13). By activating its receptor on NPY/AgRP neurons, ghrelin stimulates food intake; currently ghrelin is the only known circulating hormone to exert an orexigenic effect (14).
The other main hypothalamic areas identified as effectors of peripheral information are the paraventricular nucleus (PVN), the lateral hypothalamus perifornical area, and the ventromedial and dorsomedial nuclei (15,16). These structures are divided into two categories. The lateral area constitutes the orexigenic limb, whereas the ventromedial, dorsomedial, and paraventricular nuclei constitute the anorexigenic part of the hypothalamus. The PVN, located adjacent to the third ventricle, acts to integrate neuropeptide signals from numerous CNS regions, including the ARC and brain stem (17) . The PVN plays a major role in integration of all signaling functions that regulate energy homeostasis (18,19). This brain area seems to house neurons that mainly promote negative energy balance and play an important role in energy homeostasis, at least in part, by conveying input from the ARC to other key brain areas (20). Certainly more research is needed to fully elucidate the role PVN plays in energy homeostasis.
The dorsomedial nucleus (DMN) plays a significant role in the modulation of energy intake. Destruction of the DMN results in hyperphagia and obesity, although less dramatic than in response to VMN lesioning. Injection of orexigenic peptides, NPY, galanin, and GABA, into the DMN increases food intake (21), Similar to all other nuclei important in energy regulation, the DMN has extensive connections with other hypothalamic nuclei. It receives projections from AgRP/NPY neurons from the ARC but also contains NPY-expressing cell bodies. Administration of melanocortin agonists in the DMN has been shown to reduce both local NPY expression and suckling-induced hyperphagia in rats most likely because of proximal localization of a-MSH immunoreactive fibers to these NPY-expressing cells (22).
The lateral hypothalamic area and perifornical area (LHA/PFA) are other hypothalamic areas involved in energy homeostasis. The PFA seems to be one of the most sensitive areas for NPY-induced feeding, apparently more so than the PVN (15) . The LHA/ PFA contains melanin-concentrating hormone (MCH) expressing neurons (16) , and among the key LHA neurons involved in body weight regulation are those that express either orexin (23) or MCH (24). Data from animal studies support an important role for MCH because targeted deletion of MCH (25) or its receptor (26) causes a weight-reduced, lean, hypermetabolic phenotype whereas central administration (24) and/or transgenic overexpression of this peptide increases food intake (22,24) . The LHA/PFA also contains neurons expressing prepro-orexin and releasing the peptide products orexin A and B (also called hypocretins 1 and 2) (3,23). Orexin neurons project widely through the CNS to several areas, including the PVN, ARC, nucleus tractus solitarius (NTS), and dorsal motor nucleus of the vagus (27), i.e., to areas associated with arousal and attention as well as feeding. The mechanisms by which the MCH and orexin neurons in the LHA integrate CNS and peripheral signals to influence energy homeostasis remain to be fully clarified (3). However, major targets are currently considered the endocrine and autonomic nervous system, the cranial nerve motor nuclei, and cortical structures. Finally, neurons in the LHA (mainly orexin-containing) may play an important role in narcolepsy (28) and arguably an important role, by extension, in sleep regulation.
The ventromedial hypothalamus (VMH) has been known for many years to play a role in energy homeostasis. The VMH receives NPY, AgRP, and a -MSH immunoreactive projections from neurons in the ARC, and in turn, VMH neurons project onto both hypothalamic nuclei (e.g., dorsomedial hypothalamus) and brain stem regions (e.g., NTS). Brain-derived neurotrophic factor (BDNF), a neurotrophic factor that has recently been linked to weight loss (29), is highly expressed in the VMH, and its expression is regulated both by food deprivation and melanocortin agonists (29). Mice with reduced BDNF receptor expression or reduced BDNF signaling have increased food intake and body weight (29). Therefore, BDNF neurons in the VMH may act as an additional downstream pathway through which nutritional status and the melanocortin system modulate energy homeostasis. Finally, data from recent studies (30) strongly support the view that BDNF plays a role as an anorexigenic factor in the dorsal vagal complex.
The brain stem seems to play an important role in signal integration of energy availability (3). Caudal brainstem includes several sensors of nutrient intake and expenditure, as well as receptors of peripheral hormones, including leptin and insulin (3) . Extensive reciprocal connections exist between the hypothalamus and brain stem, particularly the NTS. The NTS is in close anatomical proximity to the area postrema, a circumventricular organ with an incomplete blood–brain barrier (3). Like the ARC, the NTS is therefore in an ideal position to respond to peripheral circulating signals, but in addition, it also receives vagal afferents from the gastrointestinal tract and afferents from the glossopharyngeal nerves (31). In addition to glucagon-like peptide 1 (GLP-1) (see below), NPY neurons from the brain stem project forward to the PVN, and extracellular NPY levels within the NTS are modulated by feeding (32). Other important structures found in the NTS include NPY-binding sites (Y1 and Y5 receptors), melanocortin system (33), and MC4R (3).
Recently, the scientific community realized that the system involving hypothalamic neuropeptide systems is far from being static. There is a rapid synaptic remodeling (34), and according to recent studies (34), changing metabolic states can cause alterations in neuronal interactions by changes of the wiring of synapses and hypothalamic metabolic circuits. In these studies, fasting resulted in a balance of stimulatory and inhibitory synapses on orexin and NPY neurons that favored increasing activity of these neurons. On the other hand, inhibitory interneurons of the same regions (neurons that would inhibit either orexin or NPY neuronal activity) exhibited a synaptic balance during fasting that would support neuronal inactivation, thereby further enhancing the activity level of orexin and NPY perikarya. These observations raise the notion that metabolic signals, leptin in particular, may have an acute effect on synaptic plasticity within the appetite centers. Recent data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone’s behavioral effects (34). Similarly, the effects of an orexigenic hormone, ghrelin, and anorexigenic hormone, estradiol, have also been studied. It appears that synaptic plasticity is not leptin-specific since rearrangement of synapses has also been observed in response to ghrelin and estradiol in a leptin-independent manner (34). These observations raised the intriguing possibility that altered synaptic plasticity could be an important way through which peripheral metabolic hormones may influence brain functions in the long term.
The CNS structures responsible for regulating energy homeostasis mediate their effects through the release of specific neuropeptides which, although grouped into orexigenic and anorexigenic subcategories, act in a coordinated manner, either synergistically or antagonistically (summarized in Table 1 ). Several orexigenic neuropeptides have been identified, which are expressed centrally and integrate peripheral signals to reduce EE and/or increase energy intake, the most important being NPY, agouti-related protein (AgRP), MCH, orexin, and galanin (GAL). On the other hand, signals of a positive energy balance are integrated centrally via anorexigenc neuropeptides, including a-melanocyte-stimulating hormone (a-MSH), cocaine- and amphetamine-regulated transcript, galanin-like peptide, the corticotrophin-releasing hormone family of peptides, serotonin, and dopamine. The above peptides are presented briefly in Table 1 .
The NTS contains NPY, melanocortin, and GLP-1 neuronal circuits. GLP-1 forms the major brain stem circuit known to regulate energy homeostasis. In the CNS, GLP-1 is synthesized exclusively in the caudal NTS, and these preproglucagon neurons also express leptin receptors. GLP1 immunoreactive fibers then project widely, but particularly to the PVN and DMN, with fewer projections to the ARC. GLP-1 receptor expression is also widespread, both within the hypothalamus (PVN, dorsomedial hypothalamus, and supraoptic nucleus) and in the brain stem. Central administration of GLP-1, either into the third or fourth ventricle, potently reduces fasting and NPY-induced food intake (35). These data have suggested a role of not only circulating but also endogenous hypothalamic GLP-1 in energy homeostasis.
The opioid system appears to play a significant role in energy homeostasis. Release of opioids, such as endorphins, during food intake could enhance the pleasure of eating. Opioids released in response to ingestion of sweet and other palatable foods can increase central opioidergic activity and exogenously administered opioids generally increase food intake (36). Microinjection of opioid agonists into the nucleus accumbens, an important part of the reward circuit, stimulates the preferential consumption of highly
Centrally expressed neuropeptides important in energy homeostasis
Factors that Factors that upregulate downregulate Peptide Receptors Expression Area expressionexpression Function
Neuropeptide YSix known NPYExpressed throughout the A state of negative energy Positive energy NPY is the most potent orexigen known,(NPY) (138) (139, receptors (main CNS, but especially in balance (142)balance, associated and repeated third ventricle or PVN140) are NPY1 and hypothalamic nuclei Ghrelin, increases the with increased leptin injection of NPY causes markedNPY5 receptors) and the locus ceruleus expression of NPY and and insulin levels hyperphagia and obesity
(141) of the brainstem AgRP in the arcuate (152)Central administration of NPY increasesCo-localized with nucleus (14) PYY inhibits NPYfood intake, decreases energyagouti related protein Corticosterone (CORT) expression in the expenditure, decreases sympathetic(AgRP) in the arcuate (143–146)arcuate nucleus via outﬂ ow to brown adipose tissue, andnucleus Hypoglycemia the Y2-receptor (13) increases lipogenesis (139, 153)(147–149)NPY stimulates basal plasma insulin and morning plasma cortisol (54) , effects which are independent of increasedfood intake Agouti-related protein Mediates its Co-expressed with NPYIncreased Ghrelin and Rising leptin and Central administration of AgRP in rodents(AgRP) effects mainly in the arcuate nucleus CORT levels (10, 156, insulin levels increases feeding and body weightby blocking (139,154,155) 157)(10, 156, 157) (159,160)a -MSH from Declining carbohydrate AgRP also affects energy expenditure andbinding to stores and thermogenesis via the TRH system, suchMC4R and hypoglycaemia that exogenous AgRP in rats results in aMC3R in the AgRP and NPYdecreased TSH and total T4 simulatingbrain (139) potentiate each other’sthe hypothyroid state present duringeffect on feeding fasting (161)behavior (158) Activation of ARC NPY/AgRP neuronspotently stimulates feeding via a numberof pathways: the orexigenic effect ofNPY released in the PVN, AgRP
Factors that Factors that upregulate downregulate Peptide Receptors Expression Area expression expression Function
antagonism of MC3R/MC4R in the PVN, and local release of NPY and GABA within the ARC to inhibit the arcuate POMC neurons via Y1 and GABA receptors, respectively Melanin-Melanin Lateral hypothalamus FastingRising leptin levels Central administration of MCH causes concentrating Concentrating (LHA) and the zona Insulin(163) hyperphagia (24) hormone (MCH) Hormoneincerta Declining fatty acid MCH knockout mice have reduced Receptor 1 levels(164,165) weight and are lean due to hypophagia (MCH1-R) and Ghrelin and glucose (139), and possibly increased energy 2 (MCH2-R) do not inﬂ uence expenditure (162) (139,162)its expression to a Mice with targeted disruption of signiﬁ cant extent (166) MCH1-R display excessive feeding, hyperactivity, increased metabolic rate, and resistance to diet induced obesity (25). This resistance to weight gain in the setting of hyperphagia suggests that MCH may promote a positive energy balance mainly by decreasing activity and energy expenditure, rather than by increasing nutrient intake Orexins (also known Orexin A has Lateral hypothalamus Similar to NPY and AgRP, Central orexin neurons express both as hypocretins) high afﬁ nity and perifornical area they are stimulated neuropeptide (mainly NPY) receptors Orexin A Orexin B for the orexin-1 orexin neurons by a negative energy and leptin receptors and hence may be receptor, which project widely through balance and by rising able to integrate actions of both CNS is highlythe CNS levels of and peripheral signals Major targets of these
expressed in the VMH. Orexins A and B have equal afﬁ nities for the orexin-2 receptor, which is expressed primarily within the PVN
Galanin (GAL) GALR1, GALR2
to areas including the PVN, ARC, NTS, and dorsal motor nucleus of the vagus and to areas associated with arousal and attention as well as feeding
Hypothalamus, primarily in the PVN and ARC nuclei, as well as the LHA and perifornical area (181) glucocorticoids and Ghrelin (23,158, 167–171)
Hypoglycaemia and insulin also exert a stimulatory effect on the expression of orexin mRNA (172,173) Leptin does not signiﬁ cantly regulate orexin levels, with obesity and hyperphagia (hyperleptinemic states) actually being associated with increased levels of these neuropeptides (167, 174–177) High-fat diets
Declining glucose levels fail to elicit changes in GAL mRNA expression (188) neuropeptides are currently considered the endocrine and autonomic nervous system, the cranial nerve motor nuclei, and cortical structures
The considerable rise in orexin mRNA observed in response to declining blood sugar and the subsequent stimulating effects of orexins on locomotor activity and searching behavior suggests a role in hypothalamic arousal (167, 172, 178–180)
Exogenous administration of GAL stimulates feeding behavior, decreases energy expenditure and decreases sympathetic nervous system activity (189)
GAL has a role in regulating carbohydrate metabolism in the setting of a high-fat diet (190)
Factors that Factors that upregulate downregulate Peptide Receptors Expression Area expression expression Function
Melanocortins are G-protein-coupled MC3R, expressed in Peripheral signals of Decrease of energy intake and increase of cleaved from receptors (MCR) many areas of the energy abundance, energy expenditure (197) proopiomelanocortin are expressed CNS and in several such as insulin and MC4R knockout mice are obese (POMC): throughout the peripheral sites, and leptin (11, 193)MC4R antagonists administered centrally a-melanocyte body MC4R, expressed In contrast to the decrease food intake dramatically (191) stimulating mostly in the CNS orexigenic peptides, MC3R knockout mice have reduced hormone (a-MSH) (192), are the receptors dietary nutrients exert lean body mass and increased fat g-MSH (191)most relevant to no regulatory control mass, despite hypophagia and normal energy regulation. Five over POMC expression metabolic rates (198) melanocortin receptors (194–196) Central administration of MC4R have been identiﬁ ed, agonists suppresses food intake, while MC1R-MC5R, administration of antagonists results in however, MC3R and hyperphagia MC4R are most likely Furthermore, several MC4R mutations to play a role in energy have been identiﬁ ed in obese homeostasis. humans (199, 200), accounting for approximately 5% of morbid obesity in children (46, 201), (201) Melanocortin agonists reduce both food intake and body weight in several mouse models of obesity (197, 202), and their role in humans is being evaluated in ongoing trials
Cocaine and No speciﬁ c Arcuate nucleus, lateral Elevated levels of Food deprivation Direct intracerebroventricular CART amphetamine receptor has hypothalamus and leptin, insulin and administration decreases nocturnal, as regulated transcript been identiﬁ ed paraventricular nuclei glucocorticoids (204) well as fasting induced food intake in (CART) to date (203) High-fat diets also exert rodents (139) a stimulatory effect Neurons synthesizing CART are on CART mRNA indirectly responsible for the effects expression of leptin through sympathetic nervous system activation (205) CART may also act as a modulator of the rebound thermogenic effect taking place in states of hypothermia (206, 207) Galanin-like peptide GALR2 (208) Arcuate nucleus GALP mRNA levels Central injection of this hormone results (GALP) increase in response in decreased feeding and body weight to leptin and food (211) restriction (209)Additionally, a thermogenic response Glucose administration has been observed following acute has been shown to administration of GALP (212)increase GALP entry into the brain (210) Corticotropin CRF receptor PVN (CRF) CRF mRNA expression The CRH family of peptides: they Releasing Hormone is tightly controlled by promote negative energy balance, they (CRH ) family of CORT levels continue to maintain tight glycemic peptides: (214, 215) control through the effects of adrenal Corticotropin steroids. (216–221) Releasing Factor CRF regulates ACTH release from the (CRF) anterior pituitary and subsequent Endogenous CRF release of CORT from the adrenal receptor ligands, glands (220, 222) the urocortins (213)
Factors that Factors that upregulate downregulate Peptide Receptors Expression Area expression expression Function
Interventional studies have demonstrated that central administration of CRF results in hypophagia, increased energy expenditure, increased blood glucose, and decreased insulin secretion
Important anorexigenic role by mediating leptin’s weight reducing effect (223) and by stimulating POMC neurons to release a-MSH (224)
5-HT 2C receptor knockout mice have decreased oxygen consumption, increased food intake and increased body weight (223). Several anti-obesity drugs act by increasing 5-HT receptor signaling
Increasing the availability of 5-HT by affecting its release and reuptake in the synaptic cleft, or the direct activation of the 5-HT receptors, reduces food consumption, whereas decreasing 5-HT receptor activation produces the opposite effect
Arena Pharmaceuticals is currently developing APD356, a new selective 5–HT2C receptor agonist for obesity. Also in development is Wyeth’s 5–HT2C agonist WAY–16390915 Catecholamines Central a1 or
Dopamine (DA) Dopamine receptor isoforms (D1–D5)
and hence dopamine
the caudate puta
men restores feeding,
while gene therapy
into either the caudate
putamen or nucleus
restores preference for
a palatable diet
Activation of 1 and, 2-adrenergic receptors inhibits food intake
Beta-adrenergic receptors are considered the most important receptors in the adrenergic family for regulation of energy expenditure in response to dietary excess. Ablation of all three b-Rs in mice results in obesity, which is largely due to lower energy expenditure, and this effect is enhanced when mice are challenged with caloric excess (48). Thus, these mice are mildly obese on a regular diet but become massively obese on a high fat diet. These data are further supported by the fact that mutations of b -Rs are clearly associated with human obesity
Plays a central role in energy intake, as seen in the abnormal feeding associated with pharmacological depletion and / or genetic disruption of dopamine synthesis (223)
Striatal extracellular DA increases with food intake in normal weight subjects (225), but in obese subjects there is reduced brain DA activity, which may predispose them to excessive food intake (225). Further studies are needed to deﬁ ne the speciﬁ c dopamine receptor isoforms (D1–D5) that will have the most signiﬁ cant weight reducing effects, while avoiding behavioral side effects or addiction
palatable sucrose and fat (37). Conversely, opioid antagonists administered into the nucleus accumbens reduce preferentially sucrose ingestion in comparison to other less palatable substances (37). Several studies indicate that there are interactions of opioids with other appetite-regulating processes (38).
Among the several novel antiobesity strategies currently under development, it was hoped that pharmacological antagonism of the anabolic cannabinoid-1 receptor could potentially be the first to come into clinical use. The cloning of the G-protein-coupled cannabinoid-1 receptor (CB1R) provided valuable information about the mechanisms of action of the principal active constituent of cannabis, d9-tetrahydrocannabinol (39) . The lipids anandamide and 2-arachidonoyl glycerol, which are known as endocannabinoids, are natural ligands for CB1R. CB1R mediates the anabolic effects of exogenous and endogenous cannabinoids (40). Anabolic and prodiabetic actions of endocannabinoids include the following: (1) in the hypothalamus, increase of orexigenic and decrease of anorexigenic neuropeptides; (2) in mesolimbic reward centers, enhancement of food palatability and reward reinforcement; (3) in the hindbrain, blunting of nausea and GI satiation signals transmitted from the vagus nerve; (4) in the GI tract, inhibition of satiation signals and potentiation of hunger signals transmitted to vagal sensory nerve terminals, as well as facilitation of nutrient absorption; (5) in adipose tissue and liver, stimulation of lipogenesis; and (6) in muscle, impairment of glucose uptake (40).
Given the major anabolic actions of CB1R, it is not surprising that pharmacological antagonism of this receptor promotes weight loss. A specific CB1R antagonist, rimonabant, was created only a few years after the receptor was discovered and was followed by the discovery of other antagonists such as taranabant. Through its actions in the hypothalamus, hindbrain, mesolimbic reward centers, and vagus nerve, rimonabant enhances anorexia, potentiates satiation signals, and lessens the motivation to consume palatable, rewarding foods. Together, these effects reduce food intake and body weight. Beneﬁcial effects of rimonabant on body weight, adiposity, and other features of the metabolic syndrome have been conﬁrmed in phase III human trials lasting up to 2 years (41–43) which led many European nations to approve this agent as a new drug for obesity. The approval in the USA has been delayed, however, owing to concerns about a potential for psychiatric side effects. It remains to be seen whether rimonabant or taranabant or both will eventually be approved for obesity and the metabolic syndrome.
According to the first law of thermodynamics, the total energy of a system plus the surroundings remains constant. Obesity can result, therefore, from a relative increase in energy intake (food) compared to EE. The regulation of EE and its role in body weight homeostasis has not been very well studied to date. Potent physiologic mechanisms maintain body weight within a narrow “set point” and regulate energy balance with accuracy in most humans (44), as demonstrated by under- and overfeeding studies (45). Certain thermogenic mechanisms, such as leptin-induced increases in EE (46,47) and diet-induced thermogenesis, a critically important antiobesity mechanism as per studies in rodents (48,49), have evolved in mammals to allow burning up of excess energy (50,51). Human studies suggest that increased sympathetic nervous system (SNS) activity, decreased parasympathetic nervous system activity, and an inferred form of physical activity known as non-exercise activity thermogenesis (NEAT) lead to an increase in EE in overfeeding states and obesity (52–55). However, many more studies are needed to determine the importance of thermogenic, antiobesity mechanisms in humans (48).
EE can be categorized into obligatory (basal) and adaptive (facultative) thermogenesis. Obligatory EE includes all processes that are involved in the maintenance of basic metabolic and physiologic processes, including the maintenance of ion gradients, muscle tone, digestion, and blood flow (standard metabolic rate). Adaptive thermogenesis includes cold and diet-induced thermogenesis. For example, although thyroid hormone (TH) is required for up to 30% of standard metabolic rate, adaptive increases in TH are required for normal cold-induced thermogenesis (56). Physical activity can also have long-lasting effects on resting metabolic rate (57). Approximate contributions of the various EE components are resting metabolic rate (70%), physical activity (20%), facultative (10%), with physical activity representing the most variable component (58).
2.2. The Role of Regulation of Energy Expenditure in the Development of Obesity
Mammals have potent homeostatic mechanisms, which maintain body weight by changing food intake and EE (59). Only relative differences in EE might explain predisposition to obesity since obese patients have increased EE when compared to lean subjects (56). Although there are data demonstrating that increased food intake causes obesity, there has been less evidence that decreased EE may specifically lead to obesity. Differences in EE have been proposed to be associated with the development of obesity over a period of years (60) while genetic factors may play a major role in controlling EE (52,61). However, other reports do not support the hypothesis that abnormal regulation of EE leads to obesity (58,62,63). For example, several studies have failed to find obesity-promoting mechanisms to explain differences between lean and obese subjects, including SNS nerve activity (64), catecholamine turnover (65), lipolysis (66), the thermic effect of food, (58) and THs (67). In summary, the hypothesis that relatively low EE contributes to the development of obesity has been supported by a few but not all studies. It remains unclear whether stimulation of EE in humans will eventually prove to be a useful approach for antiobesity therapy.
Regulation of EE depends on many factors, including physical activity, changes in energy intake/diet, THs, SNS, adrenergic receptors, futile cycles, and intermediary metabolism genes.
Increasing physical activity represents an effective method to resist obesity in the setting of increased food intake; it has effects on EE both acutely, with large increases in maximal oxygen consumption, and chronically via increased mitochondrial proliferation (68). In humans, a combination of decreased food intake and physical activity is most successful for sustained weight loss (69). Overfeeding studies in lean humans showed that the majority of increased EE in response to caloric excess occurs via increased non-exercise activity thermogenesis (NEAT), a separate category of physical activity that is related to adiposity which includes all tasks of daily living (70), and not via increases in thermic effect of food, or coordinated physical activity (55). Further research into the regulation of physical activity as a specific mechanism to control body fat stores is still needed.
Although there are limited data available based on measurements of everyday, real life physical activity at the population level, it appears that energy intake has increased and physical activity has decreased more than enough to explain the increasing prevalence of obesity in the population (71). A related controversial issue in the area is how much physical activity should be recommended for prevention of weight gain, for weight loss, and/or for prevention of weight regain after weight loss. In this respect, several studies have shown that very large increases in physical activity are necessary to avoid weight regain after weight loss (72) while very small increases may prevent weight gain (59).
The role of diet composition on body weight is an area of controversy in the field of obesity research. Diet composition can affect body weight in individuals who are in energy balance. In a recent review, Astrup et al. (73) found that body weight is reduced slightly as dietary fat content of the diet is lowered in individuals who were in energy balance. Reducing dietary fat without food restriction may affect both energy intake and EE in small ways, since voluntary intake may be lower with low- vs. high-fat diets (74,75). Increasing dietary carbohydrate and reducing dietary fat could also be expected to produce a slight increase in the thermic effect of food (75), since carbohydrate produces more thermic effect than fat does, but this remains to be conclusively shown. The impact of high- vs. low-glycemic diets as well as of protein diets on energy balance is still the focus of intensive research efforts (76,77).
Diet composition during negative energy balance
Diet composition may have different effects depending on whether subjects are in energy balance or whether they are in positive or negative energy balance. During equivalent negative energy balance, there might be little difference in altering the fat/ carbohydrate ratio of the diet and there seems to be similar body weight and body fat loss with high- and low-fat diets when total energy intake is fixed at a level below energy requirements (78). However, there are several reports of differences in weight loss with high- and low-fat diets when energy intake is not fixed (79,80), suggesting that diet composition may affect satiety or hunger during dieting. A recent meta-analysis (81) concluded that nonenergy-restricted, low-carbohydrate diets were at least as effective as low-fat diets over a period of 1 year. Lowering dietary fat has little impact during negative energy balance. Therefore, in general, low-fat diets have not been found to lead to greater weight loss than diets higher in fat content. Diet composition during positive energy balance
During positive energy balance, diet composition can have a relatively larger effect on energy balance. Studies have shown that excess energy is efficiently stored in the
body regardless of its source, but it has been proposed that excess energy from dietary fat is stored more efficiently than excess energy from carbohydrates (82). This area is of significant interest and the focus of intensive research efforts.
Thyroid hormones (TH; including T 4 and T 3) play a significant role in regulating EE. Thyroid hormones mediate ~30% of basal thermogenesis and stimulate numerous anabolic and catabolic pathways (reviewed in (83)). Low TH levels in response to dietary restriction are associated with reduced EE during weight loss and act to resist body weight change in obesity (84). These changes in TH levels are also associated with changes in EE and SNS. All these alterations are to a certain degree due to falling leptin levels in response to weight loss (84), but the extent to which falling leptin mediates the alterations in TH in response to food deprivation and whether leptin administration in replacement doses would improve weight loss maintenance remain to be seen.
The SNS is another significant regulator of EE (reviewed in (85)). b -Adrenergic receptors (AR) are apparently the most important receptors in the adrenergic family for regulation of EE in response to dietary excess but other receptors are also important in EE regulation (86). Several studies support the model of altered EE in response to caloric excess, and resistance to obesity. In most rodent models of obesity there is low SNS activity, which can be associated with propensity for future weight gain (85,87), and activation of this pathway by b-AR agonists is effective in reducing obesity in mice (88,89). Numerous attempts to alter SNS function (by surgical, chemical, immunological, and genetic means) failed to affect body weight, however, and thus the importance of SNS-mediated diet-induced thermogenesis lacks support (90–92). On the other hand, ablation of all 3 b-ARs in mice (b-less mice) results in obesity that is entirely due to lower EE, and this deficit is enhanced when mice are challenged with caloric excess (48). These results are supported by genetic studies in humans reporting mutations in b-ARs that are associated with human obesity (86,93). In contrast, the development of b-AR agonists for the treatment of obesity has failed to result in any usable compounds in studies in humans.
EE in mammals can be regulated by thermogenic futile cycles that can involve various metabolic pathways, including the glycolysis pathway (94), as well as calcium (95–97), sodium, and proton cycling in cells. Although lipogenic/lipolytic futile cycles are stimulated in white adipose tissue (WAT) in response to peroxisome proliferator-activated receptor (PPAR) agonists (98), futile cycles have not yet been shown to play a significant role in mammalian body weight regulation, however.
There is increasing evidence that EE in mammals is controlled at numerous, rate-limiting, and, in some cases, leptin-mediated steps in glucose and fatty acid metabolism. In many rodent models loss of function of key synthetic enzymatic steps in fatty acid synthesis results in increased EE, reduced body weight, and obesity resistance (99–102). In humans, polymorphisms in the rate-limiting enzyme for triglyceride synthesis are associated with lean kindreds (103). AMP kinase, which is regulated by leptin, is an emerging, central mediator of these critical steps in fatty acid metabolism and affects appetite and EE (104,105).
Many tissues have the metabolic potential to mediate thermogenesis as a specific response to increased body weight and adipose stores.
Brown adipose tissue (BAT) plays a critical role in thermogenesis and body weight regulation in rodents (106), but may not represent an attractive target for antiobesity treatment because of its apparent absence in adult humans. BAT is a highly thermogenic form of adipose tissue (107). Stimulation of b-ARs by catecholamines or synthetic b-AR agonists markedly stimulates EE, primarily in BAT (50). b-AR agonists have not been proven to be effective as potential treatment options for human obesity, because of low abundance of the b3-AR in human tissues, or lack of specificity for the human b3-AR, or intolerable side effects because of the high doses needed. These considerations have made the use of b-AR agonists for human obesity uncertain (108). High fat feeding also results in marked BAT hypertrophy and increased EE, suggesting that BAT plays a role in resisting obesity (49,50). Subsequent isolation and cloning of a 32-kDa protein, then-called thermogenin, initiated a search for the function of such proteins (uncoupling proteins, or UCPs) that uncouple oxidative phosphorylation and thus have the capacity to produce heat (109). Some studies (110,111) have supported a role for UCPs in more specialized forms of thermogenesis, but other studies have revealed controversial results. Others have emphasized the existence of a paradox: BAT is necessary for normal body weight regulation, but the major thermogenic protein, UCP-1, is not apparently absolutely required (112). This paradox may be solved by either finding another thermogenic mediator in BAT or investigating other tissues as potential mediators of diet-induced thermogenesis.
White adipose tissue (WAT) clearly participates actively in many metabolic processes
(113) via regulation of glucose uptake, lipolysis, response to adrenergic stimulation, and release of numerous cytokines (leptin, ASP, adiponectin, resistin) (114) . Furthermore, although the metabolic rate of WAT is often cited as low, strong evidence indicates that significant overall EE derives from WAT (115). Secreted WAT-specific cytokines, including leptin, adiponectin, resistin, and other substances, are reviewed in previously published papers (113). Our current understanding is that WAT can be viewed not only as a storage depot, but as an important endocrine organ that profoundly affects EE and body weight. WAT represents an important potential antiobesity target via increased EE.
Appropriate strategies for weight loss would be to either prevent positive energy balance and stop the gradual weight gain of the population or treat obesity in those already affected. This involves producing negative energy balance to produce weight loss, followed by achieving energy balance permanently at a lowered body weight. In the following paragraphs, we discuss the above approaches. The major antiobesity pathways that have been targeted for manipulation of EE include mitochondrial uncoupling, the activation of the SNS, and TH use. With the possible exception of the medicines discussed below, none of these has been successful in treating human obesity because of either intolerable side effects or lack of efficacy, as judged by prevention of further weight gain, 5–10% loss of weight, metabolic improvement, and/or long-term maintenance (116).
Compounds that short circuit the mitochondrial membrane potential, called uncouplers, had preceded the isolation and characterization of endogenous UCPs. These compounds (2,4-dinotrophenol, for example), which are effective treatments for obesity through their ability to increase oxygen consumption, have been abandoned because of a narrow therapeutic window and intolerable side effects (117).
Leptin is an adipocyte-derived cytokine that stimulates numerous pathways in the CNS, including weight loss. Exogenously administered leptin results in decreased food intake in leptin-deficient humans and, presumably via the SNS, in modest (if any) increase in EE and fat mobilization. The majority of obese human patients have elevated leptin levels in serum, however, indicating that there is resistance to leptin. The effect of exogenous leptin on body weight loss in humans is highly variable across a wide patient population, most likely because of already high leptin levels in obese patients reflecting a variable degree of tolerance or resistance to its effects (118). Although leptin-deficient patients respond markedly to leptin treatment, these patients are extremely rare (119). In addition, it is possible that certain patients with partial leptin deficiency may also respond to exogenous leptin treatment (120,121), but this remains to be studied in the future.
Activation of TH receptor bincreases metabolic rate and causes weight loss in mice, and thus may become a drug target for obesity (122). Subtype-specific compounds that are selective for a single thyroid receptor isoform are potential approaches to making antiobesity compounds (123), but this is currently only an emerging area of research.
Ephedrine is a sympathomimetic agent that increases numerous SNS activity responses, including heart rate, blood pressure, and basal metabolic rate, probably through direct activation of adrenergic receptors. Its usefulness is limited by cardiovascular side effects and relatively low efficacy in the treatment of obesity, although in combination with caffeine it may show greater efficacy (124).
Sibutramine is a nonselective NE/serotonin reuptake inhibitor that acts both as an appetite suppressant (125) and activator of SNS activity via the b3-AR (126) . Sibutramine is currently indicated for obesity treatment in the absence of known cardiovascular disease (see relevant chapter below) (127). Dose-limiting toxicity and potential side effects include increased heart rate and blood pressure. Patients should be screened for evidence of underlying atherosclerotic heart disease and need to be followed periodically while on sibutramine.
Nicotine stimulates norepinephrine release from sympathetic nerve terminals, resulting in modest (5%) thermogenesis (128). Smoking cessation may have contributed to the increase in the prevalence of obesity because of withdrawal of nicotine, which acts as both an appetite suppressant and stimulator of thermogenesis (129).
Caffeine stimulates thermogenesis by inhibition of adenosine receptors on tissues, resulting in increased intracellular cAMP levels and lipolysis (130). Caffeine may be useful, to a small extent, as a treatment for obesity, especially in combination with other compounds such as ephedrine or nicotine (128), and long-term studies have shown beneﬁcial effects of endogenous insulin sensitizers, including adiponectin, on the metabolic syndrome and diabetes. Caffeine intake is not currently included among the recommended treatments for obesity, however.
The ability of b-AR agonists to reverse obesity in rodent models led to great hopes that these could become effective treatments in humans (89). b3-Agonists, in particular, would seem to be ideal targets for drug development, because their expression is restricted to adipose tissue and they effectively reduce body weight in rodents (107) . The potential mechanisms of action of b-agonists are multiple, including increased mitochondrial function and abundance, differentiation of BAT in WAT depots, lipolysis, and increased fatty acid oxidation. However, the future of b-agonists as effective antiobesity treatments remains unclear as outlined above (131,132).
Food restriction is practically the primary driver of weight loss in humans; any diet that results in ingesting fewer calories will produce weight loss. Although it is also possible to lose weight with physical activity alone (133,134), it is difficult for most people to exercise enough to achieve a degree of negative energy balance that would result in significant weight loss. This is also why adding physical activity to food restriction produces only a minimal additional amount of weight loss (133,134). Unfortunately, weight tends to be regained in most people regardless of the composition of the diet used for weight loss (79,80). It has been estimated that long-term success in obesity treatment is about 20% or less if success was defined as maintaining a 10% reduction in body weight for at least 1 year (135). The mechanisms underlying the ability of the organism to defend a given body weight are under intensive investigation.
Although there are several studies about factors that contribute to weight loss, we have very little evidence to understand the factors that contribute to weight loss maintenance. In a descriptive study by Klem et al. (72), although most (>90%) participants reported that they used both food restriction and physical activity to lose weight, there was little similarity in the types of diets used for weight loss (72). Conversely, in this study many similarities were seen in the behaviors and strategies used to maintain weight loss. The four that stand out are as follows:
The exploding obesity pandemic certainly suggests that efficient and safe behavioral and pharmacological approaches to treat obesity are needed. Efforts to clarify the mechanisms underlying energy homeostasis have provided a pathway for identifying and studying targets for drug development in the treatment of obesity and related metabolic disorders. As an example, identifying the mechanisms underlying neuronal resistance to adiposity signals has clear therapeutic implications; drugs that prevent or reverse this resistance can be predicted to favor the defence of a reduced level of body fat. A more detailed understanding of the pathogenesis of human obesity hopefully will ultimately guide the development of efficacious treatment options that could benefit the affected individuals.
43 . Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia . N Engl J Med 2005; 353(20):2121–2134.
106. Lowell BB, Susulic V, Hamann A, Lawitts JA, Himms-Hagen J, Boyer BB et al . Development of obesity in transgenic mice after genetic ablation of brown adipose tissue . Nature 1993; 366(6457):740–
Susann Blüher and Christos S. Mantzoros
Key Words: Obesity , Metabolic syndrome , Insulin resistance , Pathophysiology , Adipokines , Body fat distribution
An epidemic of obesity is evolving not only in most industrial countries, but also in many developing countries around the world. Obesity substantially increases the risk for metabolic, cardiovascular, and orthopedic comorbidites. The degree of body fat
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_5, © Humana Press, a part of Springer Science + Business Media, LLC 2009
mass accumulation depends on several factors including ethnic background and genetic makeup, gender, and age, but also neuroendocrine, environmental and societal parameters. Gonadal steroids may play a major role in the distribution of body fat. At the onset of puberty, men become more muscular and have less fat, whereas women start to have a higher percentage of body fat in relation to their muscle mass. These differences persist throughout life and are reflected in the typical male and female fat distribution pattern. With advancing age, both gonadal steroid and growth hormone secretion decline, resulting in increased accumulation of visceral fat, particularly in men. In women, higher serum testosterone concentrations are usually associated with increased visceral fat. Thus, the decline in growth hormone and the loss of estrogen at the time of menopause may explain the relatively rapid increase in visceral fat in postmenopausal women. Differences in adipose tissue cellularity have also been suggested as a possible link between obesity and diabetes. Obese people with large subcutaneous abdominal adipocyte size are on average more hyperinsulinemic and glucose intolerant than those with a similar degree of adiposity but with relatively smaller subcutaneous abdominal adipocyte size (1).
According to the department of health(Buy now from http://www.drugswell.com) and Human Services, 30% of the US population was obese in 2001 with prevalence rates in other developed nations either being similar or following very closely. The prevalence of overweight or obesity in western populations is currently approximately 60% but among type 2 diabetic patients it is as high as 80% (2,3). It is anticipated that, if the same trend continues, more than 80% of American adults will be either overweight or obese by 2020.
In general terms, obesity is the result of excessive energy stored in fat. An increased fat mass is associated with an increase in fat cell size (hypertrophy) and/or fat cell amount (hyperplasia). Obesity leads to the development of a cluster of metabolic and other disturbances, collectively called the metabolic/insulin resistance syndrome, which include (or predispose to) lipid abnormalities, arterial hypertension, impaired glucose tolerance or diabetes, a proinﬂammatory state, and coagulation abnormalities, all of which lead in turn to metabolic and cardiovascular diseases as well as certain malignancies (4–6).
Several explanations for the development of the metabolic syndrome have been proposed, including ectopic fat accumulation, which apparently accompanies the obese state, as well as dysregulation and dysfunction of adipose tissue, which, in turn, secretes abnormal amounts of cytokines and hormones collectively called adipokines (7–9) . A major determinant in the development of the metabolic syndrome seems to be not only the total amount of energy stored as fat but also the body fat distribution, since visceral obesity is much more closely associated with the metabolic/insulin resistance syndrome than overall obesity (5,6).
This chapter focuses on pathways linking obesity to the features of the metabolic syndrome and discusses underlying pathophysiological mechanisms.
Insulin resistance, a state in which normal circulating levels of insulin fail to produce its expected physiological effects, usually refers to the reduced ability of insulin to regulate carbohydrate homeostasis by regulating glucose uptake and/or glucose production. The resistance in carbohydrate metabolism results in increased insulin production, which in turn may produce excessive effects of insulin in other pathways (5,10) . Thus, the consequences of insulin resistance are different in different tissues affected: in muscle, insulin resistance leads to impaired inward transmembrane glucose transport (11) , whereas in the liver, insulin resistance is mainly associated with increased neoglucogenesis and suppressed glycogenolysis as well as impaired liver glucose uptake (12). In adipose tissue (both visceral and subcutaneous), insulin resistance is manifested as a reduced insulin-mediated glucose uptake (13). Insulin resistance in metabolically active tissues leads to compensatory hyperinsulinemia. Other tissues affected by peripheral insulin resistance include the ovaries, where insulin resistance may result in the polycystic ovary syndrome, and vascular cells in which the development of artherosclerosis is the major complication. In addition, it is well established that insulin resistance may promote carcinogenesis in several tissues (14).
Up to 60% of the population and up to 80% of type 2 diabetics are currently either overweight or obese (3). Follow up for several years of either middle-aged women in the Nurses health(Buy now from http://www.drugswell.com) Study or men in the health(Buy now from http://www.drugswell.com) Professionals Follow-up Study has clearly shown that the risk of developing type 2 diabetes is rising in parallel with an increasing degree of overweight and obesity. In accordance, weight reduction is associated with decreased incidence of type 2 diabetes (4). In the Nurses health(Buy now from http://www.drugswell.com) Study, a weight loss of 5 kg or more reduced the risk of developing type 2 diabetes by approximately 50% (4). This observation was later also documented in interventional studies including the Diabetes Prevention Program (DPP), where an approximate 7% of weight reduction, maintained for an average duration of 2.8 years, was associated with a 58% reduction in the risk of developing type 2 diabetes in the prediabetic individuals with impaired glucose tolerance (IGT) (15).
2.3. Body Fat Distribution/Fat Storage and Secretory Capacity of Different Fat Depots
The distribution of adipose tissue is a major determinant of the metabolic risk profile. In addition, it has been proposed that the fact that functional capacity of the adipose tissue varies among subjects might offer an explanation for the incomplete overlap between the metabolic syndrome and obesity.
Although the subcutaneous adipose tissue is the site of main energy storage, when the storage capacity in subcutaneous fat is exhausted, the visceral fat takes over and lipids are also deposited in several other organs including muscle and liver. Individual and gender differences deﬁne the storage capacity of subcutaneous fat depots and thus the moment in which energy starts to be stored in visceral fat. In general, men have a lower subcutaneous fat storage capacity and start to accumulate fat in the visceral depot earlier than women (5,6). In concordance with these differences of functional capacity of adipose tissue, individuals with upper body fat accumulation or higher visceral fat mass are more insulin resistant than those with a predominantly lower body fat accumulation and more subcutaneous fat. This has been attributable not only to the increased sensitivity of visceral fat to lipolytic stimuli, but also to altered secretion of adipokines by visceral fat (16–19). Visceral fat is more active in terms of accepting and releasing free fatty acids (FFAs) and is characterized by a different pattern of adipocytokine secretion (20).
Thus, central or visceral obesity is associated more closely than overall obesity with higher risk to develop insulin resistance and related metabolic disorders and leads to an altered plasma lipid composition (5–7).
Subcutaneous fat is the main energy storage site in addition to producing certain levels of adipokines. Visceral fat cells produce excessive amounts of proinﬂ ammatory adipokines including tumor necrosis factor α (TNFα), interleukin 6 (IL-6), plasminogen activator inhibitor 1 (PAI-1), and/or decreased amounts of insulin sensitizing, antiinﬂ ammatory adipokines such as adiponectin (21–23). These differences in the gene expression proﬁle between visceral and subcutaneous fat may account for the diverging metabolic risk between the two fat depots. Out of the 1,660 genes expressed in adipose tissue, 297 (17.9%) genes have shown a twofold or higher difference in their expression between the visceral and subcutaneous fat depots. Many of these genes are involved in glucose homeostasis and insulin action, such as the peroxisome proliferator activator receptor γ (PPAR γ), or in lipid metabolism, such as the HMG CoA synthase and hormone-sensitive lipase (23).
health(Buy now from http://www.drugswell.com)y dietary patterns, including the low glycemic index diets and Mediterannean type diets have received much recognition over the past few years for their association with substantial health(Buy now from http://www.drugswell.com) benefits. A cross-sectional study evaluating plasma markers and dietary data from 987 diabetic women from the Nurses’ health(Buy now from http://www.drugswell.com) Study (NHS) revealed that women following a Mediterranean-type dietary pattern albeit older tended to have lower body mass indexes and waist circumferences, and had higher total energy intakes, physical activities, and plasma adiponectin concentrations. Of the several components of the Mediterranean dietary pattern score, alcohol, nuts, and whole grains showed the strongest association with adiponectin concentrations (24). The significance of high circulating adiponectin levels in the context of features of the metabolic syndrome is discussed later on, but women in the NHS adhering closely to a Mediterranean dietary pattern had, in addition to higher adiponectin levels, lower levels of proinflammatory adipokines, lower degrees of insulin resistance, and lower risk for diabetes and cardiovascular disease. In contrast, high glycemic index diet and higher consumption of sugar-sweetened beverages, observed mainly in relation to a Western dietary pattern, are clearly associated with a greater magnitude of weight gain and an increased risk for developing type 2 diabetes (25–27). Recent studies suggest that long-term coffee consumption is associated with a reduction in long-term weight gain and a statistically significantly lower risk for type 2 diabetes (28–30). A higher nut consumption has also been described to offer potential benefits in lowering risk of type 2 diabetes in women (31). Finally, in addition to dietary patterns, physical activity significantly improves insulin resistance, insulin sensitivity, and the metabolic syndrome, in part by altering circulating adiponectin and expression of adiponectin as well as adiponectin receptor mRNA in muscle, as discussed later on (32).
The prevalence of the metabolic/insulin resistance syndrome continues to increase with the exploding prevalence of overweight and obesity. This is the case in several racial and ethnic groups including Americans among whom the prevalence of the metabolic syndrome is estimated to be as high as 40% (2–6). Several studies have demonstrated that weight reduction through increased physical activity, pharmacotherapy, or bariatric surgery is associated with a highly significant reduced risk to develop any component of the metabolic syndrome, including impaired glucose tolerance and type 2 diabetes (15,33–35).
Emerging data strongly support the view that adipose tissue dysregulation and dysfunction might play a role of major signiﬁcance in the pathogenesis of the insulin resistance syndrome. A dysfunctional adipose tissue associated with hypertrophy of adipocytes and coupled with excessive fat deposition in muscle and liver is currently considered a “conditio sine qua non” for the development of the metabolic syndrome (5,6). These alterations lead to a derangement in the release of fatty acids, hormones, adipokines, cytokines, and other molecules as discussed in more detail below.
Mechanisms inducing a low-grade systemic inflammation have been recently suggested to be one of the putative links between obesity, adipose tissue dysfunction, and the development of insulin resistance (7,36). Although the exact signals and the mechanisms that trigger the inflammatory response remain incompletely understood, chronic inflammation is apparently not only associated with, but is also most probably causally related to the development of insulin resistance. It has been shown that accumulation of macrophages in adipocytes leads to an activation of inflammatory pathways (10,37,38). Markers of chronic inflammation such as C-reactive protein (CRP), fibrinogen, TNF α and IL-6, and/or circulating triglyceride levels are elevated in serum of obese subjects and can predict the future development of impaired glucose tolerance and type 2 diabetes (39,40).
Although the question of how the hypertrophic adipocytes are linked to the recruitment of macrophages into the adipose tissue and the establishment of a proinﬂ ammatory state remains to be fully elucidated, and the consequences of these changes are far better understood. The two most important harmful cytokines involved in this process are currently thought to be TNF α and IL-6, whereas adiponectin appears to be the most protective adipocytokine. Both harmful adipokines impair insulin signaling (at the level of the insulin receptor or at postreceptor levels including the Insulin Receptor Substrates level) as well as actions of insulin (7,41). The fact that the number of macrophages in human adipose tissue correlates positively with the degree of obesity strengthens the hypothesis that macrophage inﬁltration into adipose tissue may contribute to the development of dysregulated adipose tissue function and initiate the process of chronic inﬂ ammation (7).
A major focus of research has been the question whether dysfunctional and inﬂ amed adipose tissue can be converted into “health(Buy now from http://www.drugswell.com)y” adipose tissue again and whether the progression of metabolic dysfunction can be stopped or reversed by modulation of the inﬂ ammatory proﬁle in adipose tissue. In this context, several studies have shown that administration of thiazolidinediones (TZD), which act by binding to and activating peroxisome proliferator-activated receptors (PPAR γ), is capable of reversing inﬂ ammatory properties and lipid abnormalities besides the direct and indirect effects of TZDs to improve insulin resistance, including increase of circulating levels of adiponectin, an endogenous insulin sensitizer (42). Importantly, TZDs improve glycemic control and enhance insulin sensitivity despite the paradoxical weight gain seen with TZD treatment.
The latter seems to be attributable to the fact that TZDs may redistribute fat within the body by reducing visceral and hepatic fat mass and increasing subcutaneous fat depots. Since TZDs may also lead to ﬂuid retention, osteoporosis, and other complications, it has been proposed that development of non-thiazolidinedione, selective PPAR γ modulators (SPARMs) could hopefully lead to availability of effective medications that could result in increasing adiponectin levels and insulin sensitization without any side effects (43). INT-131, a compound in development by Intekrin is the one in the most advanced stages of development in this area.
5. IMPACT OF FREE FATTY ACIDS AND LIPID METABOLISM ON INSULIN RESISTANCE: EFFECTS OF LIPOTOXICITY
Insulin inhibits lipolysis in adipose tissue and promotes the transfer of FFAs from circulating lipoproteins to the adipose tissue. Thus, in states of insulin resistance, FFA levels increase in the circulation due to unrestrained lipolysis and decreased clearance of FFAs in the periphery; this phenomenon leads also to an increase of triglycerides (TG) (10). Circulating levels of FFAs are increased in obese subjects and have been proposed to be a major contributor to peripheral insulin resistance (44,45) initiating thus a vicious cycle. Chronically elevated serum FFA levels stimulate gluconeogenesis, induce insulin resistance at the level of liver and muscle, and impair insulin secretion in genetically predisposed individuals (43). Increased FFA levels also tend to increase triglyceride accumulation in both liver and skeletal muscle, and this correlates with the degree of insulin resistance in these tissues (46,47). Serum triglycerides, which are in a state of constant turnover, and their metabolites such as acyl coenzymes A, ceramides, and diacylglycerol also contribute toward both impaired hepatic and peripheral insulin action. In addition, nonesterified fatty acids are raised in obese subjects (both, diabetic and nondiabetic) following enhanced adipocyte lipolysis. Increased fatty acid concentrations lead to enhanced insulin secretion in the short term and significant (even total) inhibition of insulin secretion as early as 24 h thereafter (48,49). This sequence of events is frequently called lipotoxicity (50). Accumulating evidence suggests that such lipotoxicity may also be an important contributor to the pancreatic β cell dysfunction seen in type 2 diabetic patients (48,51). Since the magnitude of the effects of lipotoxicity has been questioned by some investigators, this area remains an active area of research.
As previously described, when the classical fat depots are ﬁlled to capacity, other storage depots may be used for the storage of excess fat, namely liver and muscle. The failure of adipose tissue to take up more fat absorbed by the digestive tract leads to an excessive postprandial lipid ﬂux toward muscle and liver and to a decreased clearance of triglyceride rich lipoprotein particles. The interplay of these particles with HDL and LDL cholesterol leads to the typical dyslipidemic proﬁle, whereas the increased availability of (FFAs) has direct effects on the liver (9,52).
Similar to states of energy excess leading to obesity, congenital forms of lipodystrophy in humans, i.e., states characterized by selective loss of subcutaneous and visceral fat, are also associated with metabolic abnormalities (hyperglycemia, insulin resistance, dyslipidemia) in humans (53). Insufficient adipose tissue storage capacity may in turn lead to excessive energy storage in fat, skeletal muscle, and liver. This is in turn linked to the development of severe insulin resistance in these organs. Patients with generalized lipodystrophy represent thus another model of human ectopic fat deposition. In accordance with the concept of ectopic fat accumulation as a contributing factor for obesity-associated insulin resistance and related metabolic disorders, these subjects also have abnormal secretion of proinflammatory cytokines and abnormally low circulating levels of two adipokines, i.e., leptin and adiponectin (53). The impact of an abnormal secretion pattern of those adipokines on lipid metabolism and the pathogenesis of the metabolic syndrome is discussed later on.
Recent studies support the concept that insulin resistance in one of the contributing factors to the development of dyslipidemia seen in the metabolic syndrome (10), but it has also been proposed that elevated FFAs and triglyceride levels also contribute to exaggeration of insulin resistance through a lipotoxicity mechanism. Moreover, the classic diabetic dyslipidemia could be considered as the main clinical manifestation of adipose tissue failure, i.e., lack of adipose tissue storage capacity either directly (lipoatrophy) or indirectly i.e., because existing adipose tissue stores are ﬁlled to capacity (9,54).
The discovery of the adipocyte secreted hormone leptin in December 1994 has resulted in a dramatically altered view of the role the adipose tissue plays in human physiology. In addition to its classical physiological functions (heat insulation, mechanical cushioning, storage site for triglycerides), the adipose tissue is now recognized as an active endocrine organ that produces a variety of bioactive peptides (adipokines) as well as inflammatory and antiinflammatory molecules including leptin, adiponectin, TNF α, IL-6, IL-18, CRP, PAI-1, and many others (7,9,55). Some of these molecules are almost exclusively expressed in adipose tissue (e.g., leptin, adiponectin), while others are produced by both adipose tissue and adipose tissue-resident macrophages as well as other organs or systems (e.g., TNFα, IL-6, PAI-1). With the exception of adiponectin, which is decreased, all other adipokines and inflammatory markers are increased in overweight and obese individuals.
Adiponectin is an adipocyte secreted endogenous insulin sensitizer almost exclusively expressed in adipocytes. Adiponectin expression is higher in subcutaneous than in visceral fat, which might offer an explanation for the negative correlation between circulating adiponectin levels and insulin resistance (56). This negative correlation is independent of body mass index (57). Circulating adiponectin levels are reduced in obesity, insulin resistance, and type 2 diabetes (58). In contrast to most other adipokines, adiponectin exerts profound beneficial actions including insulin sensitizing, anti-diabetogenic, anti-inflammatory/-proliferative, and anti-atherogenic effects. Up to now, two adiponectin receptors (AdipoR1 and AdipoR2) have been described and are mainly expressed in liver and muscle (59–66). Adiponectin increases fatty acid oxidation in skeletal muscle, promotes glucose utilization, and reduces hepatic glucose production, resulting thus in an increase of insulin sensitivity (9,67). Animal studies have shown that adiponectin deficiency plays an important role in the pathogenesis of insulin resistance, as adiponectin knockout mice develop insulin resistance that is reversed by adiponectin administration (61). In addition, circulating adiponectin levels correlate positively with insulin sensitivity in rodents and humans and predict the development of insulin resistance, diabetes, and cardiovascular disease as well as certain malignancies associated with obesity and the metabolic syndrome (62,63, 68–71).
In addition to its insulin-sensitizing effects, adiponectin has antiinﬂ ammatory properties and may also protect against development or progression of atherosclerosis (72,73). Thus, observational studies have shown that not only adiponectin, but also AdipoR1 and AdipoR2 are all associated with body composition, insulin sensitivity, and metabolic parameters. A health(Buy now from http://www.drugswell.com)y diet, i.e. alow glycemic index diet (74,75) and a mediterannean type diet (76) also increase circulating adiponectin levels. Intensive, but probably not moderate physical training increases circulating adiponectin and mRNA expression of its receptors in muscle, and this may in turn mediate the improvement of insulin resistance and the metabolic syndrome in response to exercise (32). A 7% reduction in body weight by lifestyle modiﬁcation for 6 months results in a signiﬁcant increase in plasma adiponectin levels in obese type 2 diabetic patients with insulin resistance (77) . These effects of weight loss and lifestyle modiﬁcation on adiponectin levels are in agreement with the observation that these interventions decrease the risk for diabetes and that subjects with high adiponectin concentrations are less likely to develop type 2 diabetes than those with lower concentrations (78).
The role of the two adiponectin receptors, AdipoR1 and AdipoR2, in the regulation of energy homeostasis and glucose metabolism is now being extensively studied in rodents and humans. The development of obesity by hypercaloric feeding in mice is associated with an altered expression/secretion proﬁle of adiponectin and its receptors in muscle and liver (79). In addition, adiponectin and both adiponectin receptors seem to be involved in the improvement of insulin sensitivity associated with ciliary neurotrophic factor (CNTF)induced weight loss (80). The mechanisms by which adiponectin improves insulin sensitivity have not yet been fully elucidated. One proposed mechanism is the activation of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle and liver, in addition to enhancing insulin-stimulated glucose uptake into fat and muscle and suppressing hepatic glucose production as well as stimulating fatty acid oxidation. Through the stimulation of fatty acid oxidation, circulating FFAs are further decreased and the actions of insulin are improved (72).
Leptin is the prototype adipokine, which is almost exclusively expressed in adipose tissue and more so in subcutaneous fat (81). According to our current understanding, leptin’s main function is to inform several organs of the organism that there is “enough energy to sustain life.” This hormone exerts direct effects in metabolically active tissues and/or indirect effects by activating hypothalamic centers via leptin receptors. Circulating leptin levels are increased in obese subjects and decreased in leaner subjects and/or in response to food deprivation (82). Its key functions include the regulation of food intake/energy expenditure, the regulation of neuroendocrine and immune function, and the modulation of glucose and fat metabolism by improving insulin sensitivity and reducing intracellular lipids (55,66).
Animal studies have shown that leptin administration has an insulin sensitizing effect in muscle cells and adipocytes (83–85). In humans, mutations of the leptin gene have been associated with severe obesity, glucose intolerance, and insulin resistance, which are reversed by leptin administration (86–88). The long-term effects of leptin replacement have been intensely studied in uncontrolled studies in patients with rare syndromes of complete, mostly congenital, lipoatrophy and severe insulin resistance or partial lipoatrophy and milder insulin resistance/metabolic syndrome induced by administration of highly active antiretrovirals (HAART) in HIV positive patients. Leptin administration in replacement doses signiﬁ cantly improved glycemia, dyslipidemia, and hepatic steatosis in these hypoleptinemic patients with severe insulin resistance (89,90) and improved lipidemia and insulin resistance in HIV positive patients (91,92).
Whether elevated leptin levels contribute toward the development of the inﬂ ammation associated with obesity, type 2 diabetes, and atherosclerosis needs to be fully elucidated. Suggested pathways include direct actions on macrophages to augment their phagocytic activity and to increase production of other inﬂ ammatory cytokines (93,94). However, initial studies in humans do not support a role for increased leptin levels in this respect. The exact role of leptin in inﬂuencing and regulating neuroendocrine and immune function as well as energy homeostasis remains a subject of intense research efforts (55,66,95).
Resistin is an adipokine that has been proposed to correlate closely with hepatic insulin resistance, and circulating resistin levels and resistin expression in adipose tissue was proposed to be increased in type 2 diabetes and obesity (96–98). However, recent data on a potential association between resistin and insulin resistance have been controversial. Additional studies are needed to fully understand the molecular and cellular mechanisms of action of this adipokine (99,100).
Visfatin is a recently discovered adipokine. It was first described in 2005 and seems to be associated to the pathogenesis of obesity and impaired glucose homeostasis. In the initial visfatin study, it was proposed that the protein is mainly produced in visceral adipose tissue and that its expression is increased in states of insulin resistance. The authors also reported that visfatin directly binds to the insulin receptor and that it excerts insulin-like effects in vivo and in vitro (101). Meanwhile other groups have reported that visfatin is also produced by a variety of other cells and that it acts as a multifunctional protein and enzyme (9). To date, the role of visfatin in adipogenesis and glucose homeostasis remains controversial. The distinct role of visfatin in the pathogenesis of insulin resistance and its impact in states of energy excess needs to be fully elucidated by carefully designed studies in the future.
Another promising adipocytokine, the role of which also remains to be fully elucidated, is retinol-binding-protein 4 (RBP4). RBP4, the only transporter protein for vitamin A, retinol, has been proposed to be elevated in obesity and type 2 diabetes and is decreased with inflammation or infection (102). RBP4 was discovered as a molecule that may regulate the expression of glucose transporter 4 (GLUT4), the most important insulin-stimulated glucose transporter, which is increased in states of insulin resistance and leads to an impaired glucose uptake into adipocytes and progressing glucose intolerance. Several but not all groups have also reported that there is an association between RBP4 and insulin resistance, obesity, and other features of the metabolic syndrome (lipid profile, HOMA index, arterial hypertension, proinflammatory markers like CRP or IL-6) (9). The exact mechanism underlying these associations needs to be studied in more detail. Since data on the role of RBP4 in humans are controversial, more studies of this molecule are clearly needed to fully understand its physiological role in energy homeostasis and insulin resistance.
7.6. Tumor Necrosis Factor a (TNFα) TNFα is a potent proinflammatory cytokine implicated in the development of insulin resistance and type 2 diabetes as well as atherosclerosis (103) . Circulating TNF α levels and/or levels of the soluble TNF α receptor, a long-term marker of TNF α systemic activation, are increased in both obese nondiabetic individuals (104) and in type 2 diabetes (105) . TNF α is structurally similar but functionally opposite to adiponectin, and these molecules are reciprocally regulated. Studies in genetically obese animals suggest that increased release of TNF α from adipocytes may play a major and direct role in the impairment of insulin action (106,107) . TNF α influences insulin signaling through impairing serine phosphorylation of insulin receptor and insulin receptor substrate-1, inhibiting thus insulin action at the organ level through autocrine and paracrine
mechanisms (108) . TNF α may also alter glucose transporter physiology and thus impair insulin sensitivity and glucose metabolism.
IL-6 is another important proinflammatory cytokine, which may also influence insulin resistance. Similar to TNF α, IL-6 regulates hepatic production of CRP and other acute phase proteins. In animal studies, IL-6 has been implicated in the development of insulin resistance in muscle and may also be involved in β cell apoptosis (109) . IL-6 levels are elevated in type 2 diabetic subjects and correlate with severity of inflammation as well as glucose intolerance (110,111). The interrelationship between the two proinflammatory cytokines, TNF α and IL-6, is complex, since not only TNF α stimulates IL-6 production and consequently CRP production, but IL-6 also exerts a feed back inhibitory effect on TNF α production (112). Intervention programs that mainly increase IL-6, such as physical activity, may have an antiinflammatory effect through suppression of TNF α, which is one of the major inducers of inflammation (113).
Plasminogen activator inhibitor-1 (PAI-1) is another cytokine that may link obesity to type 2 diabetes and cardiovascular disease. This serine protease inhibits the fibrinolytic cascade. Elevated PAI-1 levels cause an imbalance accelerating the atherosclerotic process (114). Adipose tissue is one of the major sources of PAI-1, and circulating levels are elevated in obese and diabetic subjects. It has also been noted that hyperinsulinemia, which usually accompanies insulin resistant states, is a potent stimulus for PAI-1 production by adipose tissue (115,116).
Obesity-related insulin resistance and the metabolic syndrome is a complex state the pathophysiology of which remains poorly understood. The prevalence of the metabolic syndrome has been increasing during the past few years, and this has generated a tremendous research activity in this area. However, even more intense research is needed to further elucidate the molecular and cellular mechanisms underlying this important public health(Buy now from http://www.drugswell.com) problem and to potentially provide better therapeutic options for the patients suffering from this syndrome.
1. Weyer C,FoleyJE,Bogardus PA , Tataranni REP. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type 2 diabetes independent of insulin resistance . Diabetologia 2000; 43: 1498–1506.
2 . Tunstall-Pedoe H. Preventing Chronic Diseases. A Vital Investment: WHO Global Report. Geneva: World health(Buy now from http://www.drugswell.com) Organization, 2005, pp 200. CHF 30.00. ISBN 92 4 1563001. Also published on http:// www.who.int/chp/chronic_disease_report/en/Int J Epidemiol 2006.
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116. Alessi MC, Peiretti F, Morange P, et al . Production of plasminogen activator inhibitor1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease . Diabetes 1997;
Eirini Bathrellou and Mary Yannakoulia
Key Words: Childhood Obesity, Dietary intake, Physical activity, Behavior modification, Parental involvement, Low-glycemic diets
Childhood obesity has been recognized as a public health(Buy now from http://www.drugswell.com) priority for many countries. Prevalence of overweight has increased in Europe, the United States, and many other parts of the world (1–3). During the last decades, all industrialized and many low-income countries have doubled or even tripled their numbers, while countries which traditionally confronted undernutrition problems now encounter obesity problems as well (4). In addition, comparisons of the distribution of body mass index (BMI) between earlier and later
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_6, © Humana Press, a part of Springer Science + Business Media, LLC 2009
Fig. 1. Interaction of the parameters targeted for the management of children’s overweight .
studies show a greater shift in the upper part of the distribution, implying that heavier children have now become even heavier (5).
This global epidemic would not have justiﬁed the alarming interest of scientists, health(Buy now from http://www.drugswell.com) care professionals, and the general public on the prevention and treatment of childhood obesity, if it were not for its multilevel consequences. Obesity has both short and long-term health(Buy now from http://www.drugswell.com) consequences, affecting the child both in its present and future adult life (6). One of the most well documented short-term effects refers to the cardiovascular risk factors, namely hypertension, dyslipidemia, endothelial dysfunction, hyperinsulinemia, and insulin resistance (7–9). Metabolic syndrome, a clustering of cardiovascular risk factors frequently seen in adults, has also been identiﬁed in children and it correlates with obesity status (10–12). Childhood obesity also has harmful psychosocial and economic consequences (13,14), and it tracks well into adulthood (15,16).
Even though genetic predisposition and environmental inﬂuences interact to cause excess weight, the accelerated increase in the prevalence of childhood obesity during the last decades cannot be explained by a genetic shift (17). It rather reﬂ ects profound changes in environmental factors, resulting in positive energy balance. Thus, treatment should focus on the modiﬁable factors of the energy equilibrium, i.e., dietary intake and physical activity. Several approaches have been proposed for inducing dietary and physical activity changes, along with behavior modiﬁcation and the participation of parents (Fig. 1 ). Purpose of this chapter is to discuss these approaches in the context of lifestyle interventions in managing overweight in children.
Although hypocaloric diets have been widely used in achieving weight loss, the optimal type of diet remains unknown. Research in adults indicates that short-term success can be achieved with diets varying widely in composition, from very low-fat to very low-carbohydrate content; however, most individuals experience weight regain over the long term (18–21). In children, combinations of calorie limits and food exchange systems have been applied. The traffic light diet is a food exchange system, first developed by Epstein and colleagues (22); foods are divided into three categories according to their energy and fat content: greens can be consumed freely, oranges should be consumed with caution, and reds should be avoided. A daily or weekly number of servings for each of these food groups is, then, recommended. The traffic light diet has evolved in terms of number of calories or red foods (23), allowing for a higher calorie limit (up to 1,500 kcal) and more red foods (24), while modified versions have been developed using either a specific diet (25,26) or no calorie limit (27).
A low energy diet, ranging in calorie content from 1,200 to 2,000 kcal, applied either as a tailored or an exchange-based regime, has been also used (25,28–32). Most of the recommended diets so far were characterized as “prudent” or “balanced,” with a caloric deﬁ cit of around 30% less of the reported intake or 15% less than the estimated required intake, providing approximately 30% of calories from fat. However, available evidence from randomized trials do not support current recommendations for low-fat energy restricted diets (33).
Less restrictive dietary interventions have been successfully undertaken. Recent guidelines suggest that dietary treatment should focus on eating behaviors, such as breakfast skipping and meal frequency, eating out and portion size (34), rather than calorie restriction per se. The need for putting less restraint in the dietary manipulation is also supported by evidence indicating that ﬂexible, not rigid, dietary restraint is associated with lower BMI values and a more successful long-term weight control, both in adults and children (35,36), as well as by concerns that obese children are at high risk for developing eating disorders or show resistance to treatment (37). Under this perspective, nonprescription approaches, promoting the concept of “eating differently, not necessarily less” and a health(Buy now from http://www.drugswell.com)y eating (38,39), or focusing on ad libitum low-glycemic diets have been investigated. With regard to the latter, Ebbeling et al. examined the long-term effects of a reduced glycemic load, nonenergy restricted diet with those of a reduced-fat, externally imposed hypocaloric diet, in a small-scale randomized controlled trial of 16 obese adolescents (40). Over 12 months, BMI and fat mass signiﬁcantly decreased in the reduced-glycemic load diet group, whereas neither measure changed signiﬁcantly in the conventional diet group. Furthermore, insulin resistance, as assessed by the homeostasis model assessment, increased less with the low-glycemic load diet, even after statistical adjustment for BMI. These ﬁndings indicate that reducing the glycemic load or index of a diet, without externally imposing energy restriction, may yield several health(Buy now from http://www.drugswell.com) beneﬁ ts in young people. Adolescents, in particular, may more easily adhere to such a dietary pattern, as they may feel less hungry and also more ﬂexible in their dietary choices, thus reaching more easily a negative energy balance allowing for a weight loss.
Including a physical activity-related component in weight management programs for overweight children is of major importance, because of its obvious effect on energy balance and its beneficial impact on cardiovascular risk factors, even independently of weight reduction (41,42). Recommendations regarding physical activity in children target a generally active lifestyle, and suggest at least 60 min of moderate intensity physical activity, if possible everyday, and not exceeding 2 h of daily screen time (34) . Within school setting, individual or team noncompetitive sports, and recreational activities are suggested (43), as well as an active participation in physical education classes (44).
Results of a 10-year follow up suggest that physical activity as a lifestyle change is a promising, feasible, and convenient way for managing overweight in children (45). On the one hand, both structured and nonstructured activities have been beneﬁcial in reducing BMI in children (46). On the other hand, targeting sedentary activities has been proven at least as (47) or even more (48) effective in reducing percent overweight in children compared with targeting an increase in physical activity per se. It has, further, been proposed that changes in physical activity habits in children reach a plateau: a set-point of physical activity competence may exist within each child, irrespective of the environmental opportunities (49), acting as a mediator of his/her physical activity levels.
Both dietary intake and physical activity constitute the result of numerous corresponding behaviors; therefore, studying behavior in the context of combating obesity has attracted great scientific interest. The beneficial effect of adding behavioral modification techniques in a conventional program for the treatment of childhood obesity has been originally described in the early 1990s (50,51), and has been confirmed many times ever since (52). Behavioral and cognitive-behavioral components have been considered as important components of the lifestyle treatment programs (53) . There is also some preliminary evidence proposing that the use of a motivational interviewing style by pediatricians and dietitians may be another promising office-based strategy for preventing overweight children to become obese (54), even though its efficacy as a treatment modality has not been proven yet (55).
Several techniques have been used in the childhood obesity treatment programs under the aim of modifying eating patterns and increasing physical activity levels. These include contracting, self-monitoring, stimulus control, goal setting, reinforcement, parental training, homework exercises, problem solving, and overcoming stressful situations. Although it is difﬁcult to isolate a speciﬁc technique and assess its effectiveness, some of them have been evaluated and proven to have a beneﬁcial effect in pediatric populations, like self-monitoring (56), stimulus control (57) , and problem-solving (58).
Parents affect children’s eating and physical activity patterns by several means, namely formulating children’s environment, being role models, and controlling their dietary intake (59). Parental participation is considered as an essential component in a program aiming at modifying child’s lifestyle habits and combating obesity. A great body of research investigates the most effective parental role. Epstein and colleagues highly supported the role of parents as targets for managing their own weight along with their child’s effort to manage body weight (45): a significantly higher reduction in percent overweight of children was revealed after 10 years of follow-up when parents and children were both targeted for weight loss compared to when only children were targeted. Israel et al. found that when parents were helpers, rather than cotargets, the therapeutic outcome was slightly enhanced (60). Moreover, training children in self-regulatory techniques compared with assigning parents most responsibility for change was proven essential in maintaining percent overweight loss after treatment (29). In the studies of Golan and colleagues, parents were the exclusive agents of change, without any direct child involvement (61). It was found that this approach was more efficient in managing children’s weight compared with the approach of children being the exclusive agents.
As studies are not conclusive with regard to the most effective parental role or the exact degree of parental involvement, recommendations so far suggest a rather supportive role of parents, with less involvement as the child gets older (17), and this is the most widely adopted approach (25,32,39,62,63).
The structure of the programs targeting childhood obesity varies greatly. In most cases, therapeutic programs are conducted in groups (25,60,62–65), and seldom in individual sessions (28,39) or in conjunction (38,57). Although data comparing individualized and group treatment are scarce, there seems to be a slight advantage in favor of the group format. Goldfield et al. (66) compared the effectiveness of the same family-based behavioral treatment conducted only in groups or in a mixed format, combining group and individualized sessions. As weight outcomes did not differ between the two approaches, group only format was proven more cost-effective. Moreover, Braet and Van Winckel (39) found a favorable long-term tendency for the group approach, when it was compared with an individualized, and to a summer camp approach. Diverging from the conventional setup, and in the context of applying a more cost-effective approach with greater generalization and dissemination, innovative delivery approaches using media technologies have also been evaluated. Frequent telephone and mail contact were proven feasible and effective in promoting use of behavioral skills for weight control in a group of adolescents, when compared with a single-advice typical care session (67). An interactive Website-based behavioral treatment was effective in improving some weight-related parameters in the short term, but Web hits decreased dramatically in the long-term (68).
The length of the intervention ranges from 6 weeks to 18 months, with the majority of studies lasting between 3 and 6 months (23). Sessions are usually conducted on a weekly basis. Combinations of weekly and biweekly (29) or even monthly (45) sessions has also been applied, lengthening intervention time. As long-term effectiveness is the ultimate outcome of obesity interventions, addressing weight loss maintenance postinterventionally emerges as a necessity, in accordance to adult studies which, in this regard, propose the extension of treatment contact or content (69) . Wilﬂey et al. (70) successfully tested the efﬁcacy of adding an active maintenance phase following a standard family-based behavioral treatment, in a randomized controlled trial. Interestingly, both maintenance methods studied, i.e., behavioral skills or social facilitation, produced many beneﬁ ts, either in weight or psychosocial outcomes, compared with no maintenance approach. Still, a decline in treatment effectiveness was observed, regardless of the treatment duration or content, suggesting the need for the development of continuous care models for children.
As the degree of obesity of children who participate in weight control programs has increased over the last two decades, in accordance to the increase in childhood obesity rates observed in the general population, it is not surprising that more children in the earlier studies were below the criteria for being at risk for overweight or overweight after treatment (71). As young people nowadays live in a more obesogenic environment, promoting greater food intake and more sedentary activities, contemporary programs need to be more powerful to produce treatment effects similar to those observed in the studies during 1970s and 1980s.
A lot of work needs to be done in reﬁning existing programs. An earlier review concluded that the reduction of sedentary behavior appeared to be the most effective intervention for achieving and maintaining weight loss in children and that the degree of parental involvement in childhood obesity interventions remains uncertain (72) . A more recent pointed out that, although the combination of diet, exercise, behavioral techniques, and parental involvement remains the cornerstone for improving the effectiveness of a weight-loss program, there is still a limited number of studies including a control group (73). Furthermore, most studies are small and noncomparable, they report short-term results with limited generalizability, rarely reporting health(Buy now from http://www.drugswell.com) outcomes, such as cardiovascular risk factors (74). With regard to diet, interventions including dietetic treatment can be effective, but there are not many quality studies undertaken to date, with adequate long-term follow-up data (23). Therefore, there is an urgent need for well-designed randomized trials to evaluate the lasting effectiveness of dietary interventions
(33) and lifestyle programs.
In conclusion, for the time being, the combination of the four parameters discussed, i.e., dietary and physical activity changes, behavioral modiﬁcation and parental support, constitute the best available therapeutic strategy for childhood obesity. The most recent recommendations on the treatment of childhood obesity are based on this scheme (34), proposed though to be implemented at different settings, from a primary care provider to a multidisciplinary team, and supplemented when needed with more invasive strategies.
p. 1156 – 7 .
62 . Levine, M.D., et al. Is family-based behavioral weight control appropriate for severe pediatric obesity? Int J Eat Disord , 2001, 30(3): p. 318 –28.
Frank B. Hu
Key Words: Obesity , Weight loss , Diet , Exercise , Fat , Carbohydrate , Protein , Whole grains , Fruits andvegetables , Glycemic load
Obesity has reached epidemic proportions in the US. On the basis of the NHANES 2003–2004 data, the prevalence of the conditions in US adults is estimated at 66.3 and 32.2%, respectively (1). The prevalence of morbid obesity (BMI > 40 kg/m 2 ) is approximately 4.8%. There has been a marked upward trend in obesity over the past several decades in both men and women.
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_7, © Humana Press, a part of Springer Science + Business Media, LLC 2009
Overweight and obesity are central to the metabolic syndrome and the single most important risk factor for type 2 diabetes. Obesity is associated with increased incidence of cardiovascular disease, cancer, and mortality from all-causes. The US Surgeon General in 2001 issued a Call to Action, pointing out that “Overweight and obesity may soon cause as much preventable disease and death as cigarette smoking” in the United States. Approximately 300,000 US deaths a year currently are associated with obesity and overweight (compared with more than 400,000 deaths a year associated with cigarette smoking) (2).
Obesity is a complex problem resulting from a combination of genetic, behavioral, environmental, cultural, and socioeconomic inﬂuences. Although behavioral and environmental factors are considered primary determinants of obesity, speciﬁ c dietary lifestyle factors have not been clearly deﬁned. In this chapter, we review epidemiologic and clinical evidence regarding dietary factors and several popular diets and their effects on obesity and weight loss. Also we review epidemiologic evidence regarding the role of physical activity in preventing weight gain.
Hypothetically, as dietary fat is the most energy-dense macronutrient in the diet, overconsumption of energy could result if food intake is not regulated (3). In addition, the enhanced palatability of high-fat foods could impact regulation of the volume of food intake, leading to increased energy intake and weight gain. Findings from short-term feeding studies have also suggested that as carbohydrate produces a greater thermogenic effect than fat, dietary fat might be used more efficiently and accumulate as body fat (4). However, when studies are extended to 4 days, no differences in stored energy is observed, which would not be the case if fat truly is being used more efficiently relative to carbohydrate. Over 20 years ago, Flatt (5) proposed that carbohydrate intake is regulated, unlike fat, therefore individuals on high-fat diets in theory consume more energy than those on low-fat diets to obtain required amounts of carbohydrate. To date, few data exist that support these claims, and the hypothesis itself is flawed since excess carbohydrate intake can be converted to fat, which is then stored (3).
Although several cross-sectional studies suggested a positive association between dietary fat intake and obesity, few prospective cohort studies have examined long-term relationships between dietary fat and body fatness or weight gain, and among those that have, the results have been highly inconsistent (6,7). These studies have varied considerably in size, duration of follow-up, age groups, covariates adjusted in the statistical analyses, and dietary assessment methods.
In a 6-year study of 361 Swedish women, Heitmann and colleagues (8) found a signiﬁcant association between high dietary fat intake and BMI in predisposed women (P = 0.003) but not obese women with lean parents or lean women with or without obese parents. There was a relationship between dietary fat and BMI in genetically predisposed women after adjustment for total energy intake, smoking habits, physical activity, and menopausal status, but subgroup analysis was limited by the very small sample size (n = 56).
A much larger study by Field and colleagues (9) examined the association between dietary fat and 8-year weight gain among 41,518 women in the Nurses’ health(Buy now from http://www.drugswell.com) Study (NHS). Data showed a positive relationship between weight change and increased intake of animal fat, saturated fat, and trans fat, especially in overweight women. There was a weak positive association between total fat consumption and weight gain, no association with increases in percentages of energy from mono or polyunsaturated fats, and no evidence that parental weight status modiﬁed the relationship between dietary fat and weight gain. The effects of fat on body weight vary according to type of fat. These differences may reﬂect biological actions of these fats on insulin resistance and fat accumulation. In that the amount of energy provided by different types of fat is the same, the varied effects may also reﬂect confounding of the association between diet and body weight by other dietary and lifestyle factors.
Only one prospective study (of 16, 587 US men aged 40–75 in the health(Buy now from http://www.drugswell.com) Professionals’ Follow-up Study) has examined the association between dietary fat intake and 9-year change in waist circumference. Multivariate analyses by Koh-Banerjee and colleagues (10) found that total fat intake was not associated with gain in waist circumference. However, a signiﬁcant association was found between increasing consumption of trans fat and gain in waist circumference, even after further adjustment for concurrent changes in BMI. Although confounding by other dietary factors related to high intake of trans fat (e.g., fast-food and breakfast habits) cannot be ruled out, these data suggest potentially detrimental effects of trans fat on fat accumulation.
To date, a large spectrum of randomized trials have been published that offer a less confounded evaluation of low-fat diets in relation to body weight than the many ecologic and cross-sectional studies that have examined this association (see review by Malik and Hu (11)). A metaanalysis (12) of 28 short-term trials suggests that a 10% decrease in total energy from fat can reduce bodyweight by 16 g/day, which is extrapolated to a weight reduction of 8.8 kg by 18 months and 23.4 kg by 4 years (3). Longer-term trials, however, do not substantiate these predictions. In a qualitative review by Willett (3) , several clinical and intervention trials of the effect of low-fat diets (ranging from 18 to 40% of energy) on weight, including nine long-term trials ranging from 12 to 24 months, were evaluated. This review suggests that diets lower in fat can result in modest reductions in body weight in the short-term but studies lasting for 1 year or more show that 18–40% of energy intake from fat has a negligible effect on body weight (3).
Similar ﬁndings were observed in the Women’s health(Buy now from http://www.drugswell.com) Initiative Dietary Modiﬁ cation Trial (WHI) (13), a randomized intervention trial comparing an ad libitum low-fat dietary pattern with usual diet in 48,835 postmenopausal women in the US with a mean follow-up of 7.5 years. The intervention group was instructed to reduce total fat intake to 20% of total energy intake by increasing fruit, vegetable, and whole grain consumption, and received intensive behavioral modiﬁcation sessions led by nutritionists. The control group received a copy of Dietary Guidelines for Americans (14) and followed their usual diet. Neither group was given instructions to lose weight. Overall results suggested that although the intervention group lost weight in the ﬁrst year compared with the control group (2.2 kg; P < 0.01), the difference in weight loss between the two groups was negligible at the end of follow-up (year 9) over an average of 7.5 years
(0.4 kg at 7.5 years; Fig. 1 ) (13).The authors suggest the trial provides evidence that fat restriction does not lead to weight gain, refuting claims that low-fat, high-carbohydrate
Age 50-59, y Age 60-69, y Age 70-79, y
Mean Difference, kg
4 3 2 1 0 –1 –2 –3 –4
Fig. 1. Differences from baseline in body weight by low-fat diet vs. usual diet, and age at screening. The error bars indicate 95% CIs. Numbers at baseline for intervention and control in the 50- to 59-year group were 7,206 and 10,797, respectively; 60–69 years, 9,086 and 13,626; 70–79 years, 3,249 and 4,871. Adapted from (13).
diets are driving the obesity trend (13).However, few older women are supposed to gain weight. A major limitation of the study was that the authors did not differentiate between types of fats and carbohydrates.
Low-fat, high-carbohydrate diets generally produce higher postprandial glucose and insulin responses. However, similar to total fat, the total percentage of energy derived from carbohydrates in the diet has generally not been found to predict diabetes risk. Metabolic consequences of carbohydrate intake depend not only on their quantity but also on their quality. The glycemic response of a given carbohydrate load depends on the food sources, which has led to the development of the glycemic index (GI), ranking foods by their ability to raise postprandial blood glucose levels (15). The GI quantifies the glycemic response by a standard amount of carbohydrates from a food relative to the response by the same amount of carbohydrates from white bread or glucose. The overall GI of a diet has been found to be associated with an increased diabetes risk in some prospective observational studies (16). However, the relevance of the concept of GI is indirectly supported by the reduction in diabetes incidence observed with acarbose, an alpha-glucosidase inhibitor that slows down the digestion of carbohydrates (17).
Effects of carbohydrate-rich foods on insulin resistance and diabetes risk may also depend on ﬁber content and type. Several epidemiologic studies found that diets rich in whole grains or cereal ﬁber may protect against type 2 diabetes (16). Controlled feeding studies have found beneﬁts of whole grains, when compared with reﬁ ned grains, on insulin sensitivity and glucose metabolism. This effect may be partially mediated by positive effects on body weight – studies generally support an inverse association between intake of whole grains and body weight (18). In addition, ﬁber tends to slow down gastrointestinal absorption, resulting in a lower GI of whole-grain products compared with their reﬁned-grain counterparts, but other mechanisms by which whole grains inﬂuence glucose metabolism are likely to play a role as well, e.g., short-chain fatty acid production and micronutrient content.
|a||Weighted Mean Difference, kg||Favors||Favors||b||Weighted Mean Difference, kg||Favors||Favors|
|(95% CI)||% Weight||Low Carb||Low Fat||(95% CI)||% Weight||Low Carb||Low Fat|
|Brehm et al,18 2003||–4.0 (–6.6 to –1.4)||20.2||Foster et al,19 2003||–2.8 (–6.5 to 0.9)||27.4|
|Foster et al,19 2003||–3.7 (–6.6 to –0.8)||18.2||Stern et al,21 2004||–2.0 (–5.0 to 1.0)||34.6|
|Samaha et al,20 2003||–3.9 (–6.2 to –1.57)||21.5||Dansinger et al,232005||1.2 (–1.5 to 3.9)||38.0|
|Yancy et al,22 2004||–5.5 (–8.1 to –2.9)||20.0|
|Dansinger et al,23 2005||0.4 (–2.2 to 3.0)||20.1|
|Overall (95% CI)||–3.3 (–5.3 to –1.4)||Overall (95% CI)||–1.0 (–3.5 to 1.5)|
|Heterogeneity P=.02||Heterogeneity P=.15|
|Inconsistency I2=65%||–9||–6 0–3||63||Inconsistency I2= 48%9||–9||–6 0–3||63 9|
|(95% UI, 7%-87%)||Weighted Mea||n Difference, kg||(95% UI, 0%-85%)||Weighted Mea||n Difference, kg|
Fig. 2. Weighted mean differences in weight loss after ( a) 6 months and (b) 12 months of follow-up from a metaanalysis (30) comparing the effects of ad libitum low-carbohydrate diets versus low-fat energy-restricted diets on weight loss. Adapted from (19).
Given the vast popularity of low-carbohydrate diets, a large number of studies, mostly randomized controlled trials, have been conducted to evaluate the efficacy of carbohydrate-restricted diets compared with fat-restricted diets on weight loss. A metaanalysis
(19) compared the effects of ad libitum low-carbohydrate diets (allowing a maximum intake of 60 g of carbohydrates per day or 10% energy) with those of low-fat ( 30% energy), energy-restricted diets on weight loss (19). In total, five randomized controlled trials (n = 447) were analyzed, with 6–12 months follow-up. The authors found that after 6 months, participants randomized to a low-carbohydrate diet had lost more weight than those randomized to a low-fat diet (weighted mean difference 3.3 kg, 95% CI −5.3 to −1.4 kg) (19). Notably, after 12 months this difference dissipated (weighted mean difference −1.0 kg, 95% CI −3.5 to 1.5 kg; Fig. 2 ) (19). This metaanalysis also compared the effect of the two dietary patterns on cardiovascular disease risk factors and found that after 6 months triglyceride and HDL cholesterol level changes were more favorable in the low-carbohydrate diet group, but total cholesterol and LDL cholesterol level changes were more favorable in the low-fat group. Overall, existing trials of low-carbohydrate diets/high-fat diets have shown greater short-term weight loss (within 6 months) than low-fat diets; however, most studies have been small and inconclusive. Similar findings have been shown for low-carbohydrate/high-protein diets (generally 25% energy) (20).
The Mediterranean dietary pattern emphasizes moderate consumption of fat (~40% energy) primarily from foods high in monounsaturated fatty acids, such as olive oil and encourages consumption of fruits, vegetables, tree nuts, legumes, whole grains, and fish as well as moderate consumption of alcohol (21). A review of trials assessing the effect of the Mediterranean diet on disease prevention identified three studies that evaluated change in body weight (22). Of these, only the trial by McManus et al. (23) was able to provide sound evidence for a beneficial role of the Mediterranean diet on weight loss. In their trial, individuals were randomized to either a moderate-fat energy-restricted diet (35% energy from fat) or a low-fat energy-restricted diet (20% energy from fat). After 18 months, the moderate-fat group had decreases in body weight (4.1 kg), BMI
(1.6 kg/m2), and waist circumference (6.9 cm) while the low-fat group had increases of
2.9 kg, 1.4 kg/m2, and 2.6 cm, respectively (P < 0.001). After extending the study for
an additional year, mean weight loss in the moderate fat group was significantly greater than that in the low fat group, illustrating the sustainability of a Mediterranean dietary pattern compared with traditional low-fat recommendations. Though compelling as they are, these results need to be further substantiated, and it should be noted that the dropout rate among participants was relatively high. Similarly a study by Esposito et al. (24), which randomized individuals with the metabolic syndrome to either a prudent diet (total fat < 30% energy) or Mediterranean diet, found that after 2 years, mean (SD) body weight loss was higher in patients in the Mediterranean diet group (4.0 [1.1] kg) than in the low-fat diet group (1.2 [0.6] kg; P < .001). However, it is difficult to differentiate whether these findings are a consequence of the more intensive weight loss counseling received by the Mediterranean diet group relative to the low-fat diet group. Of particular interest was the finding that levels of inflammatory markers were significantly reduced in individuals on the Mediterranean diet compared with individuals on the low-fat diet. Such findings have recently been corroborated by Estruch et al. (25) who evaluated the short-term effects of two ad libitum Mediterranean diets (supplemented with either 1 L/week of free virgin olive oil or 30 g/day of free tree nuts (walnuts, almonds, and hazelnuts)) versus those of an ad libitum low-fat diet on intermediate markers of cardiovascular disease. Compared with participants in the low-fat diet group, after 3 months those in the two Mediterranean diet groups had decreased systolic and diastolic blood pressure, blood glucose levels, and inflammatory markers and increased HDL levels. Despite much higher amounts of dietary fat in the Mediterranean diet groups, supplemented with olive oil or nuts, there was no difference in body weight between the intervention and low-fat groups.
One of the most desirable features of the Mediterranean diet relative to traditional low-fat diets is its ability to improve cardiovascular disease risk factors. However, given the large number of carbohydrate-rich foods consumed in the Mediterranean diet, such a dietary pattern should include mostly low-GI carbohydrates. Though not explicitly studied, it has been suggested that traditional Mediterranean diets may enhance weight loss by providing a sustainable dietary pattern that offers a variety of health(Buy now from http://www.drugswell.com)y, portion-controlled, palatable foods.
Substantial evidence from epidemiologic studies and clinical trials indicates that high nut consumption has beneficial effects on blood lipids and cardiovascular risk (16) . A major concern is that because of their high fat content and high energy density, higher consumption of nuts may cause weight gain and obesity. However, several cross-sectional analyses of large cohort studies, including the Adventist health(Buy now from http://www.drugswell.com) Study (26) and the NHS (27), have shown that people who consume nuts regularly tend to weigh less than those who rarely consume them.
A 28-month prospective study conducted in Spain found an association between higher nut consumption and lower risk of weight gain. Compared with those who never or almost never ate nuts, participants who ate nuts two or more times per week had a 31% (relative risk, 0.69; 95% CI, 0.53–0.90) lower risk of gaining at least 5 kg during the follow-up. Overall, participants who frequently consumed nuts gained an average of 0.42 kg less than those who rarely consumed nuts (28). In the NHS, nut consumption was inversely associated with risk of type 2 diabetes after adjustment for age, BMI, family history of diabetes, physical activity, smoking and alcohol, and total energy intake (29). The multivariate relative risk of women who consumed nuts at least ﬁve times per week (1 oz. serving size) compared with those who never/almost never ate nuts was 0.73 (95% CI, 0.60–0.89, P for trend <0.001). Sixteen-year average weight gain was also slightly lower among those who consumed nuts at least ﬁve times per week compared with those who rarely ate them (6.2 kg vs. 6.5 kg, respectively).
Several trials of nut consumption without constraints on body weight have shown no signiﬁ cant weight changes in groups assigned higher consumption of nuts (30) . Three months of follow-up in the PREDIMED Study, which was conducted in Spain, found that Mediterranean diets supplemented with tree nuts improved cardiovascular risk factors but did not lead to weight gain when compared with a low-fat diet (25) . Wien and colleagues (31) also demonstrated that substitution of almonds (84 g/day) for carbohydrates in a formula-based low-calorie diet resulted in greater weight loss during a 24-week intervention among 65 overweight and obese adults.
These epidemiologic and clinical trial data indicate that in free-living subjects, higher nut consumption does not cause greater weight gain; rather, incorporating nuts into hypocaloric diets may be beneﬁcial for weight control. The mechanisms for these observations are unclear but could be related to higher amounts of protein and ﬁ ber in nuts, which may enhance satiety and suppress hunger (32). In dietary practice, the majority of energy contained in nuts appears to be balanced by reductions in other sources of energy, especially carbohydrates. This may explain the lack of predicted weight gain in nut-supplemented diets (33). Increased fecal loss of fat due to incomplete mastication of nuts leads to loss of available energy; this has also been suggested as an explanation for the lack of expected weight gain among those who eat nuts (30).
Grains are staple foods in most societies. In traditional diets, grain were typically consumed either in whole intact form or as coarse flours produced from stone grinding. Grinding or milling using modern technology produces fine flours with very small particle size. Milling also removes most of the bran and much of the germ. The resulting refined grain products contain more starch but lose substantial amount of dietary fiber, vitamins, minerals, essential fatty acids, and phytochemicals. Because of loss of the outer bran layer and pulverization of the endosperm, refined grains are digested and absorbed more rapidly than whole grain products and tend to cause more rapid and larger increases in levels of blood glucose and insulin. Thus, whole grain products such as whole wheat breads, brown rice, oats, and barley usually have lower glycemic index (GI) values than refined grains (12). Whole grains are also rich in fiber, antioxidant vitamins, magnesium, and phytochemicals.
During 12 years of follow-up in the NHS, Liu and colleagues (34) examined the relationship between changes in intakes of dietary ﬁber and whole or reﬁ ned-grain products and weight gain. Increased consumption of whole grains was associated with a lower mean 4-year weight gain (1.58 kg in the lowest quintile and 1.07 kg in the highest quintile; P for trend < 0.0001). In contrast, increased intake of reﬁned grains was related to greater weight gain (from 0.99 to 1.65 kg; P for trend <0.0001). These ﬁndings are consistent with those in a related study on associations between whole-grain, bran, and cereal-ﬁ ber consumption and weight in a cohort of men from the HPFS (35). During 8 years of follow-up, increased whole-grain intake was inversely associated with long-term weight gain (P for trend <0.0001). There was also a dose–response relationship; each 40 g/day increment in whole-grain intake from all foods reduced weight gain by 0.49 kg. Bran from fortiﬁed-grain foods further reduced the risk of weight gain ( P for trend = 0.01) by
0.36 kg for every 20 g/day increase in consumption. Correction for measurement errors in assessing dietary changes strengthened these associations (each 40 g/day increment in whole-grain intake from all foods reduced weight gain by 1.1 kg).
Sugar-sweetened beverages have received growing attention as potential contributors to the obesity and diabetes epidemic because of dramatically increased consumption in the past several decades. Energy contained in beverages seems less well detected by the body, and subsequent food intake is poorly adjusted to account for the energy intake from beverages. Sugar-sweetened beverages have been associated with weight gain in clinical studies and observational studies among children and adults (36). The high sugar loads from sugar-sweetened beverages may also have detrimental effects on glucose metabolism leading to diabetes, beyond their potential contribution to obesity. In the Nurses’ health(Buy now from http://www.drugswell.com) Study II, a higher consumption of sugar-sweetened beverages was associated with a greater magnitude of weight gain and an increased risk for development of type 2 diabetes in women (37) (Fig. 3 ). After adjustment for potential confounders, women consuming one or more sugar-sweetened soft drinks per day had an RR of type
Weight (in Kg)
80 78 76 74 72 70 68 66
low-high-high low-high-low high-low-high high-low-low
1991 1995 1999 Year
Fig. 3. Mean weight in 1991, 1995, and 1999 according to trends in sugar-sweetened soft drink consumption in 1,969 women who changed consumption between 1991 and 1995 and either changed or maintained level of consumption until 1999 . Low and high intakes were deﬁ ned as £1 per week and ³1 per day. The number of subjects were: low–high–high = 323, low–high–low = 461, high–low–high = 110, and high–low–low = 746. Groups with similar intake in 1991 and 1995 were combined for estimates for these time points. Means were adjusted for age, alcohol intake, physical activity, smoking, postmenopausal hormone use, oral contraceptive use, cereal ﬁber intake, and total fat intake at each time point. Adapted from (37).
Sugar-sweetened soft drink consumption
multivariate + BMI
Fig. 4. Multivariate relative risks (RRs) of type 2 diabetes according to sugar-sweetened soft drink consumption in the Nurses’ health(Buy now from http://www.drugswell.com) Study II 1991–1999. Multivariate RRs were adjusted for age, alcohol (0, 0.1–4.9, 5.0–9.9, 10+ g/day), physical activity (quintiles), family history of diabetes, smoking (never, past, current), postmenopausal hormone use (never, ever), oral contraceptive use (never, past, current), intake (quintiles) of cereal ﬁber, magnesium, trans fat, polyunsaturated:saturated fat, and consumption of sugar-sweetened soft drinks, diet soft drinks, fruit juice, and fruit punch (other than the main exposure, depending on model). Adapted from (37).
2 diabetes of 1.83 (95% CI: 1.42–2.36; P < .001 for trend) compared with those who consumed less than one of these beverages per month. The RR for extreme categories further controlling for BMI was 1.39 (95% CI: 1.07–1.76; P for trend = 0.012) (Fig. 4 ). This finding suggests that BMI accounted for about half of the excess risk.
Midlife weight gain is a widespread phenomenon in most populations. Hill and colleagues (38) estimated that US adults have been gaining an average of 0.45–0.90 kg/ year in the decades since the epidemic of obesity started. Likewise, Brown and colleagues (39) estimated that middle-aged Australian women add an average of 0.5 kg/ year. For most people, midlife weight gain reflects gain in body fat, sometimes accompanied by loss of lean body mass with aging. Because weight loss and maintenance are very difficult for obese individuals, finding ways to prevent age-related weight gain is of critical importance.
Over the 4-year follow-up period in the health(Buy now from http://www.drugswell.com) Professionals’ Follow-up Study (40) men who increased vigorous exercise (including jogging, running, lap swimming, bicycling and rowing, calisthenics and racquet sports) to 1.5 h/week, decreased TV viewing, and stopped eating between meals, lost an average of 1.4 kg, compared with a weight gain of 1.4 kg among the overall population. Those who maintained a relatively high level of vigorous physical activity over time (at least 1.5 h/week) had the lowest prevalence of obesity as well as the smallest increase in body weight (Fig. 5 ). These data suggest that increasing and maintaining vigorous activity and decreasing TV use are important to prevent weight gain over 4 years.
Schmitz and colleagues (41) examined the longitudinal relationship between changes in physical activity and weight gain during 10 years of follow-up among 5,115 black
Maintain Increase Decrease Maintain Low High Activity Activity Activity Activity
Fig. 5. Prevalence of obesity (BMI 27.8) over time for different patterns of recreational vigorous physical activity. This ﬁgure is based on 3,666 nonsmoking, non-hypertensive, and nonhypercholesterolemic men aged 45–54 years (in 1986). Adapted from (40).
and white men and women aged 18–30 years at baseline in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. After adjustment for secular trend, age, clinic site, education, smoking, alcohol intake, parity, percentage of energy intake from fat, and changes in these variables over time, increasing physical activity was signiﬁ cantly associated with decreasing weight gain in all four race and sex subgroups. Speciﬁ cally, increasing high-intensity activity (requiring 6 MET hours) by 2 h/week offset observed weight gain for all groups but black men. The beneﬁts of exercise in preventing weight gain were much greater for obese subjects than for those of normal weight at baseline. In addition, an increase in physical activity in the 2–3 years of follow-up was associated with a slowing of weight gain during the subsequent 5-year follow-up; the average attenuation of 5-year weight gain was approximately 1 kg among those who increased their activity in the ﬁrst 2–3 years of follow-up (by 1 h/week of high intensity activity) relative to those who decreased their activity. These results suggest that increasing physical activity slows long-term weight gain.
In a subsequent analysis of data from the Nurses’ health(Buy now from http://www.drugswell.com) Study (42), we examined the relationship between walking, sedentary behavior (especially prolonged TV watching), and risk of obesity and type 2 diabetes among 50,277 health(Buy now from http://www.drugswell.com)y nonobese women at baseline in 1992. During 6 years of follow-up, 3,757 (7.5%), the women who had a BMI of less than 30 kg/m2 in 1992 became obese (BMI 30 kg/m2). In the multivariate analyses adjusting for age, smoking, exercise level, dietary factors, and other covariates, each brisk walk for 1 h/day was associated with a 24% (95% CI, 19–29%) reduction in obesity, and standing or walking around at home (2 h/day) with a 9% (95% CI, 6–12%) reduction in obesity. In contrast, each 2 h/day increment in TV watching was associated with a 23% (95% CI, 17–30%) increase in obesity; and each 2 h/day increment in sitting at work was associated with a 5% (95% CI, 0–10%) increase in obesity. There was a signiﬁcant association between brisk walking and reduced risk of type 2 diabetes. Conversely, time spent watching TV was associated with increased diabetes risk. It was estimated that in this cohort, 30% (95% CI, 24–36%) of new cases of obesity and 43% (95% CI, 32–52%) of new cases of diabetes could be prevented by adopting a relatively active lifestyle (<10 h/week of TV watching and 30 min/day of brisk walking).
Although diet is widely believed to play a major role in obesity, the impact of specific dietary factors remains elusive. Cumulative epidemiologic and clinical-trial evidence indicates that there is no “magic bullet” for weight control. Rather, many individual dietary factors each exert a modest effect on body weight, and over time, cumulative effects of small changes in daily energy balance lead to weight gain and obesity (43). Although dietary fat has long been considered the main culprit behind obesity, large prospective cohort studies and long-term randomized clinical trials have not demonstrated a major role of dietary fat in obesity. In contrast, emerging evidence suggests potential weight control benefits by lowering refined carbohydrates and glycemic loads, but prospective data are limited. Increasing consumption of protein is also thought to be of potential benefit; however, long-term data on protein and body weight are lacking.
Currently, there is no conclusive evidence that one popular diet is superior to another in long-term weight control. Clearly, one diet does not ﬁt all. Thus, when prescribing such diets to patients, it is important to consider cultural habits and food preference to maximize long-term adherence (11) . For most patients, rapid weight loss should not be the goal for dietary therapy. Instead, dietary recommendations should target gradual and sustained weight loss and long-term beneﬁts on cardiovascular health(Buy now from http://www.drugswell.com). Toward this end, one should choose health(Buy now from http://www.drugswell.com)y sources of fats and whole grain products, which are known to be cardio-protective and may also enhance weight loss. Substitution of health(Buy now from http://www.drugswell.com)y sources of protein for reﬁned carbohydrates and added sugar can be also beneﬁ cial for body weight and cardiovascular risk factors. Such macronutrient choices underpin the role of Mediterranean-style diets in improving cardiovascular disease risk and reducing major chronic diseases.
Compelling evidence supports that sedentary lifestyle indicated by prolonged TV watching is an important risk factor for obesity and type 2 diabetes, whereas increasing physical activity is associated with weight maintenance and a lower risk of obesity and type 2 diabetes. There are at least two explanations for the observed positive association between TV watching and diabetes risk. First, TV watching is directly related to obesity and weight gain, probably due to lower energy expenditure (i.e. less physical activity) and higher caloric intake. Second, participants who spent more time watching TV tended to eat more red meat, processed meat, snacks, reﬁned grains, and sweets and less vegetables, fruits, and whole grains. Such an eating pattern, which is linked to commercial advertisements and food cues appearing on TV, may adversely affect diabetes risk.
Most of adults in the US do not engage in regular exercise and substantial proportion of the population is completely sedentary. Also, past several decades have seen an increasing trend of sedentary behaviors, especially prolong TV watching. The combination of lack of exercise and increasing sedentary behavior at least partially contributes to the increasing epidemic of obesity and type 2 diabetes in the US and worldwide. Public health(Buy now from http://www.drugswell.com) campaign is urgently needed not only to promote increasing physical activity but also to reduce sedentary behaviors especially prolonged TV watching in both adults and children.
Given the obesogenic environment in which we live, characterized by the abundance of energy dense, processed, and highly convenient foods and sedentary lifestyle, we should realize that without changing our nutrition and physical activity environment, for most people, the effects of any kind of weight loss or maintenance diets are difﬁ cult to sustain (11) .
11 . Malik V.S. , Hu F.B. Popular weight-loss diets: from evidence to practice . Nat Clin Pract Cardiovasc Med 2007 ; 4 : 34–41.
Mary Yannakoulia, Evaggelia Fappa, Janice Jin Hwang, and Christos S. Mantzoros
Key Words: Metabolic syndrome, Weight loss, Lifestyle intervention, Diet, Physical activity, Adherence, Behavior modification
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_8, © Humana Press, a part of Springer Science + Business Media, LLC 2009
The metabolic syndrome (MetSyn), also known as syndrome X or insulin resistance syndrome, constitutes a constellation of symptoms, including obesity, insulin resistance/ glucose intolerance, dyslipidemia, and hypertension, and it is associated with a two to fourfold increase in cardiovascular morbidity and stroke (1). The increasing prevalence of MetSyn is concurrent with the alarming increase in the prevalence of obesity and type 2 diabetes. On the basis of the US population data from 1988 to 1994, the prevalence increased from 6.7% among participants aged 20 through 29 years to 43.5 and 42.0% for participants aged 60 through 69 years and aged at least 70 years respectively, reaching an overall percentage of 24.5% (2). Although there has been a controversy surrounding the exact definition of the syndrome, there is incontrovertible evidence that the risk factors associated with the MetSyn should and need to be addressed in concert. In this chapter, the risk factors will be summarized and the literature examining prevention and clinical management of the syndrome will be discussed.
2. DEFINITION AND PATHOPHYSIOLOGY OF THE METABOLIC SYNDROME
Although several criteria exist, most criteria include metabolic risk factors, such as abdominal/central obesity, hypertriglyceridemia, low levels of high density lipoprotein (HDL) cholesterol, hypertension, and elevated fasting glucose levels. Gerald Reaven first described “syndrome X” in 1988 proposing insulin resistance to be the critical factor of the syndrome, predisposing patients to hypertension, hyperlipidemia, and type 2 diabetes mellitus (3). Ten years later the World health(Buy now from http://www.drugswell.com) Organization published the first criteria for the syndrome (4). Since then, a number of definitions have been proposed (5–7). They could be categorized in two groups depending on the leading cause of the syndrome, being either visceral obesity or insulin resistance. The different definitions may lead to research and clinical problems, such as difficulties in comparability between studies or misclassification of patients.
The pathophysiology of the MetSyn is complex and remains, in most part, unknown. A full review of the current literature is beyond the scope of this chapter (8) Brieﬂ y, increased abdominal fat correlates with dyslipidemia (9–13), insulin resistance, and hyperinsulinemia (14) via mechanisms involving increased free fatty acids (15,16) and/or changes in levels of adipokines, such as adiponectin (17–21), resistin (22–24), and leptin (25–28). These factors, along with the proinﬂammatory state associated with obesity (29,30), may create an unfavorable proatherogenic milieu (31).
Park and colleagues identiﬁed risk factors associated with the MetSyn, including older age, postmenopausal status, Mexican American ethnicity, higher body mass index, current smoking, low household income, high carbohydrate intake, no alcohol consumption, and physical inactivity (32). Few randomized control trials speciﬁ cally examining incidence or resolution of MetSyn have been conducted so far (33–44); however, there is overwhelming evidence showing that management of the individual components of the syndrome can delay or prevent the onset of diabetes, hypertension, and cardiovascular disease.
3. PREVENTION OF RISK FACTORS FOR METABOLIC SYNDROME: THE ROLE OF PHYSICAL FITNESS/ACTIVITY AND OF DIETARY FACTORS
A cornerstone of prevention lies in avoiding excess body weight (45). Excess body weight increases the risk for diabetes (46–49), hypertension (50,51), and cardiovascular disease (49,52). An in-depth examination of the current treatment options for obesity can be found in Chaps. 15 and 16. In addition to decreasing the risk of adverse metabolic sequel, weight loss is also associated with decreased levels of inflammatory markers (53–57).
Several observational studies revealed associations between physical fitness and likelihood of death from cardiovascular disease. Blair et al. examined 10,224 men and 3,120 women for an average of 8 years follow-up and found that the rate of mortality was 64/10,000 person-years in the least fit men, compared with 18.6/10,000 person-years in the most fit men (58). Corresponding values for women were 39.5/10,000 person-years to 8.5/10,000 person-years. These trends remained significant after adjustment for age, smoking habits, cholesterol levels, systolic blood pressure, fasting blood glucose levels, parental history of coronary heart disease, and follow-up interval. The same scientific group has subsequently published several similar prospective studies showing that low fitness was an independent predictor of mortality in all body mass index groups after adjustment for other mortality predictors (59).
Another prospective cohort study followed 936 women who required coronary angiography for a median of 3.9 years (60). Self reported higher physical ﬁ tness scores were found to be associated with fewer coronary artery disease (CAD) risk factors, less angiographic CAD, and lower risk for adverse cardiovascular events. Furthermore, asymptomatic men with low cardiorespiratory ﬁtness levels have been shown to be more likely to develop MetSyn (61).
Most studies to date suggest that exercise confers additional health(Buy now from http://www.drugswell.com) beneﬁ ts beyond those achieved from weight loss or changes in body fat ratios. Chronic exercise is associated with improvements in triglycerides (62,63), and even a single bout of exercise has been shown to induce favorable changes in lipid metabolism of health(Buy now from http://www.drugswell.com)y men (64). Physical training reduces skeletal muscle lipid levels and insulin resistance regardless of body mass index (65,66). In addition, exercise may also exert favorable effects on adipokines, such as adiponectin and other inﬂammatory markers, without signiﬁ cant changes in body weight (67,68).
Several dietary parameters have been related to MetSyn risk factors. Regarding lipid metabolism, trans-fatty acids are associated with increased low density lipoprotein (LDL) and decreased HDL cholesterol levels (69), whereas omega-3 fatty acids, in the form of fish oils, were effective in lowering triglyceride levels (and blood pressure) in people with mild hypertension (70). Even though there has been a controversy among studies regarding the effect of polyunsaturated fatty acids consumption on glycemic control (71,72), substituting saturated for unsaturated fatty acids increases insulin sensitivity in health(Buy now from http://www.drugswell.com)y men and women (73). Additionally, it has been shown that trans- fatty acids increased risk of diabetes (74). However, restricting saturated fatty acids and replacing with carbohydrates leads to lower HDL levels as well, so as to keep fat consumption relatively high and at the same time avoiding adverse effects on health(Buy now from http://www.drugswell.com), substituting saturated with mono or polyunsaturated fat seems to provide the optimal result (75).
On the topic of carbohydrates, it seems that glycemic and insulinemic responses to ingestion of carbohydrates depend on the glycemic index or load (76). More precisely, subjects in the highest quintile of glycemic load diet compared with lowest quintile subjects had higher triglyceride and lower HDL cholesterol levels (77,78). High glycemic index foods increase the demand for insulin, creating additional stress on beta-cell function and impairing glucose tolerance (79) . Alternatively, low/moderate carbohydrate diets (from 60 g of carbohydrates/day to 40% of energy from carbohydrates) were associated with improvements in HDL cholesterol and triglycerides compared with high carbohydrate or low fat diets; however, changes in LDL cholesterol were not in favor of low as opposed to moderate carbohydrate diets (80,81). A decrease in glycemic load with the use of acarbose, an alpha-glucosidase inhibitor that slows the digestion and absorption of starch, led to a signiﬁcant decrease in blood pressure and an increased reversion of impaired to normal glucose tolerance (82,83).
Regarding alcohol consumption, 30 g/day of alcohol intake reduced fasting insulin concentration and triglyceride concentration, and increased insulin sensitivity compared with no consumption (84). A prospective cohort from the Quebec Cardiovascular Study followed 1,966 cardiovascular heart disease free men for 13 years and found that men who consumed ³15.2 g of alcohol/day had elevated plasma HDL cholesterol concentrations (P < 0.001), and lower plasma concentrations of insulin (P = 0.01), C-reactive protein (P = 0.01), and ﬁ brinogen ( P < 0.001) than men who consumed <1.3 g of alcohol/day (85). On the contrary, high (greater than 3 drinks/day) alcohol consumption is associated with hypertension, but this association has not been consistently shown with moderate amounts of intake (86).
Beyond individual nutrients or foods, holistic approaches targeting overall lifestyle changes provide interesting results. The Diabetes Prevention Program randomized trial compared the effects of placebo, metformin, and intensive lifestyle intervention (including moderate intensity physical activity such as brisk walking for at least 150 min/week) on prevention of the MetSyn in 3,234 subjects with impaired glucose tolerance. After 3 years, the cumulative incidence of MetSyn was 51, 45, and 34% in the placebo, metformin, and lifestyle groups, respectively (87). Incidence of the MetSyn was reduced by 41% in the lifestyle group and by 17% in the metformin group, compared with placebo. Interestingly, the effects of lifestyle intervention on MetSyn prevention appeared to be more strongly related to decreased waist circumference and improvements in blood pressure as opposed to dyslipidemia. The Finnish Diabetes Prevention Study, similarly, found that intensive lifestyle intervention resulted in improved glucose levels, lipid markers, and body mass index after 3 years compared with controls (88).
The high prevalence of the MetSyn and its ability to detect people at risk for cardiovascular disease or type II diabetes mellitus led the National Cholesterol Education Program to publish, in 2001, clinical management guidelines. Recommendations include weight reduction and increase in physical activity as first-line intervention beyond this, specific treatments are proposed against the lipid and the nonlipid components of the MetSyn (6). Long-term lifestyle changes constitute, therefore, the cornerstone for the management of MetSyn.
A few studies have evaluated the efficacy of lifestyle modification in resolving the syndrome. In the majority of them, weight reduction was the main goal and, most likely, the underlying mechanism leading to improvement in MetSyn parameters. Weight loss was found to favorably affect all the individual components (51,89,90): it is associated with a significant improvement in glucose control and lipid and nonlipid abnormalities (33,34). Ten percent weight loss, compared with lower rates, has been documented to result in greater reductions in the MetSyn components, with patients going beyond the 10% reduction experiencing greater short and long-term (16 months) benefits (35). Interestingly, benefits from weight loss may be present even at high posttreatment body mass index levels (³ 30 kg/m 2) (36,91).
Caloric restriction along with a low-fat or a high omega-3/low saturated fatty acids diet were found to have a beneﬁ cial effect on the MetSyn (37–39). A hypocaloric, prudent dietary pattern, rich in fruits and vegetables, consumed for a period of 24 weeks, has also been successfully applied for the management of MetSyn (40). Furthermore, great energy deﬁ cits, achieved by very low calorie diets, with or without exercise, resulted in favorable changes to the components of the MetSyn (36,41), as did the supplementary use of orlistat, a pancreatic lipase inhibitor, for achieving energy restriction (42).
Research is limited with regard to the effect of dietary manipulation of macronutrient content in patients with MetSyn. Although some evidence support the view that the modest weight loss, rather than the macronutrient composition per se, induces changes in MetSyn parameters (44), there are studies that have found improvements in blood lipid profile and pressure by modifying macronutrient composition of the diet but not energy balance and keeping stable body weight (92,93).
Although people on a low-fat, high-carbohydrate diet have greater odds of having MetSyn, compared with those on a low-carbohydrate, high-fat diet (94), this is in disagreement with data from patients having the MetSyn. When a high-carbohydrate, low-fat diet was compared with a high-fat and protein, low carbohydrate diet, all the components of MetSyn decreased signiﬁcantly with both diets (except of HDL cholesterol, which remained unchanged) (95). On the basis of the fact that low-carbohydrate diet was associated with a greater decrease in the prevalence of hypertension and hypertriacylglycerolemia, it has been proposed that tailoring dietary interventions to the speciﬁ c presentation of the MetSyn may be the best way of reducing the risk factors for cardiovascular disease (95).
Apart from the effect of individual macronutrients, dietary patterns have also been examined in relation to MetSyn parameters. In one study, consumption of a Mediterranean-style diet was shown to improve endothelial function and signiﬁcantly reduce markers of systemic vascular inﬂammation in MetSyn patients, even with modest weight loss (43). Participants in the Mediterranean diet intervention showed a reduction in the components of the syndrome to that extent that the overall prevalence of MetSyn was reduced by approximately one half. The authors commented that, as the analysis was adjusted for changes in body weight, the overall reduction in the prevalence of the metabolic syndrome probably represents a conservative measure. Adoption of a Mediterranean-style diet rich in whole grains, fruits, vegetables, legumes, walnuts, and olive oil is a safe and effective strategy in reducing both the prevalence of MetSyn and its associated cardiovascular risk. Furthermore, another dietary pattern, the DASH diet (Dietary Approach to Stop Hypertension), has been shown to favorably inﬂuence MetSyn parameters, and particularly blood pressure. Adoption of a DASH diet, in the context of an intensive behavioral intervention including the established lifestyle modiﬁ cations for lowering blood pressure, may be a key feature to achieve a decline in blood pressure in MetSyn patients (96).
The beneficial effects of physical activity on MetSyn are well established: increases in physical activity improve individual metabolic parameters or combinations of them (33,37,97), either directly or by promoting weight reduction. MetSyn resolved in 30% of patients after 20 weeks of supervised aerobic exercise training (98). In addition, 8 weeks of low-intensity endurance exercise induced a moderate decrease in insulin resistance (99). As weight loss constitutes an important therapeutic goal for the treatment of MetSyn, increase and maintenance of physical activity levels further contributes to this goal by supporting weight loss maintenance (100).
The type of physical activity varies greatly among studies, from nonprescribed ad libitum physical activity (35,36,43) to supervised exercise, specified in terms of duration and type (33,34,37–40). Resistance and aerobic exercise have been proven to be equally effective in improving metabolic parameters (101). Concerning, the intensity and amount of aerobic exercise, a modest amount of moderate-intensity exercise, in the absence of dietary changes, signiﬁcantly improved MetSyn and, thus, supported the recommendation that adults should get 30 min of moderate-intensity exercise every day (102). Furthermore, there was an indication that moderate-intensity may be better than vigorous-intensity exercise for improving MetSyn.
Changes in physical activity were among the principal goals of most lifestyle interventions for MetSyn, in addition to dietary modiﬁ cations (33–40,43). In one study, adding an exercise component to a dietary intervention led to a signiﬁcant reduction only in systolic blood pressure compared with the nonexercise, diet-only group (33) . Alternatively, adding a dietary modiﬁcation component to an exercise intervention had beneﬁ cial effects on several parameters, namely weight reduction, fasting glucose levels, and diastolic blood pressure (37). Furthermore, combining diet and exercise had additive effects on the resolution of MetSyn compared with either treatment alone (103). It should be pointed out, however, that, in those interventions that include both exercise changes and dietary modiﬁcations, improvements in MetSyn components were not speciﬁcally attributed to the exercise or the dietary component (33–40,43), and we cannot draw conclusions on the relative signiﬁcance of these two lifestyle parameters.
The effect of physical activity has also been examined in relation to the maintenance of changes. To further improve MetSyn parameters or maintain achieved changes, the addition of exercise at the end of a weight-reduction program has been found to be as effective as dietary therapy alone; in other words, physical activity did not confer further beneﬁt to the parameters studied (91). The authors postulated that either the exercise dose was too small or the adherence to the exercise sessions was not at the prescribed levels. Nevertheless, there is accumulating evidence in support to that long-term maintenance of weight loss is facilitated by regular physical activity (104–106). This is of great value considering that body weight is an important factor affecting MetSyn parameters.
Adoption of a health(Buy now from http://www.drugswell.com)y balanced diet requires behavioral changes in relation to meal planning, food selection, food preparation, portion control, and appropriate responses to eating challenges. Long-term adherence is required and its importance has been extensively discussed in the context of obesity or diabetes (107–109). However, evidence regarding MetSyn is limited. Greater adherence has been correlated with greater decreases in Met-Syn parameters (40). Anderssen et al. (39) reported significant improvements in MetSyn components in the group of “good responders,” i.e. those belonging to the highest tertile of change for body weight and oxygen uptake. This finding could be translated as “best adherence, best results.”
With regard to maintenance, although signiﬁcant changes in MetSyn parameters have been observed in the short-term (34,37,40,109), in the absence of posttreatment booster sessions, subjects tend to maintain only part of the changes achieved or, for some components, they even return to their initial status (38). On the contrary, when active follow-up was included in the treatment (as three to four follow-up visits per year for 20 months), a further improvement in MetSyn components was achieved (35).
As noted earlier, low adherence to prescribed exercise sessions was suggested to mediate the modest changes observed in the components of the MetSyn (91). In a study by Singh et al. (40), control and intervention groups were given written advice to increase physical activity, whereas the intervention group also participated in a supervised exercise program. Improvement in the MetSyn components was achieved only in the intervention group, consistent with the ﬁnding that this group experienced a greater increase in physical activity, i.e., greater compliance to the program. Therefore, most investigators preferably use supervised exercise treatment (33,34,37–39), instead of an ad libitum exercise component (35,36,43).
There is a growing body of literature supporting the important role of diet and physical activity in the prevention and management of the MetSyn. To date, most of the lifestyle interventions had a favorable effect on the MetSyn; dietary changes constitute the core of the treatment, weight reduction plays a key role, and exercise confers an additional favorable effect. Nonetheless, it is of major importance to explore strategies to improve adherence and ensure that patients achieve and maintain lifestyle changes.
6 . Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486–97.
11 . Grundy SM. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. Clin Cornerstone 2006;8 Suppl 1: S21–7.
106 . Schoeller DA, Shay K, Kushner RF. How much physical activity is needed to minimize weight gain in previously obese women? Am J Clin Nutr 1997 ; 66 : 551 – 6 .
Key Words: Cancer , Diet , Food consumption , Incidence , Mortality , Physical activity , Obesity , Prevention , Recommendations , Trends
Cancer confers a major disease burden worldwide, but there are marked geographical variations in cancer incidence overall and in cancers of specific organ sites. Worldwide, approximately 10 million people are diagnosed with cancer annually, and more than 6 million die of the disease every year; currently over 22 million people in the world are cancer patients. The total cancer burden is highest in affluent societies, mainly due to a high incidence of tumors associated with Western lifestyle and smoking, i.e., tumors of the prostate, breast, colorectum, and lung (1). Cancer incidence and mortality between low risk and high risk countries differs by several fold.
Trends for cancer mortality during 1950–2000 and cancer incidence in 2002 for the United States, Europe, and Japan are presented in Figs. 1 and 2 . Cancer incidence and mortality have been steadily rising throughout the century in most areas of the world. However, over the last few years in North America and in Western Europe, some decline
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_9, © Humana Press, a part of Springer Science + Business Media, LLC 2009
Greece Sweden USA Japan
Fig. 1. Time trends in mortality from all cancer and incidence rates of all cancer in 2002 among women.
in cancer mortality has been observed. Thus, age-standardized cancer mortality rates for all neoplasms in the USA declined by 3.1% in both sexes combined between 1990 and 1995 (1). Approximately half of the decline was attributed to the leveling of lung and other tobacco-related cancer epidemics, and the rest to several factors, including reduced exposure to occupational carcinogens, prevention and early diagnosis, and improved treatment. In Europe as well as in North America and Japan, between 80 and 90% of lung cancers in men, and between 55 and 80% of lung cancers in women, are attributable to cigarette smoking. Taking into account all tobacco-related cancers, between 25 and 30% of all cancers in Europe and the USA are due to tobacco smoking. Because of the length of the latency period, tobacco-related cancers observed today are mainly related to cigarette smoking patterns several decades ago (1). Another major factor, identified almost three decades ago as a factor contributing to cancer risk, is diet (2).
Comparing the incidence and mortality rates between the different countries we have to keep in mind that Greek data may be less reliable than Swedish, and the data from the United States and from Japan are reasonably reliable. The Greek data may overestimate
Greece Sweden USA Japan
Fig. 2. Time trends in mortality from all cancer and incidence rates of all cancer in 2002 among men.
actual rates, because regional registries exist in the more developed regions that are usually characterized by higher cancer rates (3).
Later we present time trends for prostate, breast, and colorectal cancer mortality between 1950 and 2000 as well as incidence of these cancer sites in 2002 for the four chosen countries representing different geographical regions (Figs. 3 – 5 ). The differences between Japan and Sweden as well as the USA are striking for prostate and breast cancer incidence and mortality, with Sweden having the highest and still increasing prostate cancer mortality (4).
While breast cancer mortality is decreasing in the USA and Sweden, and there is a suggestion that the increasing trend in Greece has changed, the opposite trend is seen in Japan. The difference in mortality rates between the USA and Japan has changed from almost ﬁve-fold in the 1950s to about 2.5-fold in 2000.
Mortality rates for colon cancer in the USA, although systematically decreasing since the mid 1980s, are still higher than in Japan and Greece where rates continue to increase.
Rate per 100 000 Rate per 100 000
140 120 100 80 60 40 20 0
Fig. 3. Time trends in mortality rates from prostate cancer and incidence rates of prostate cancer in 2002.
Rate per 100 000
25 20 15 10 5 0
Fig. 4. Time trends in mortality rates from breast cancer and incidence rates of breast cancer in 2002.
Greece Sweden USA Japan
Fig. 4. (continued)
1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000
Greece Sweden USA
Fig. 5. Time trends in mortality rates from colon cancer and incidence rates of colorectal cancer in women and men in 2002.
Already in 1964, an expert committee of the World health(Buy now from http://www.drugswell.com) Organization concluded that many common fatal cases of cancer could be potentially prevented by changes in lifestyle and other environmental factors, including dietary deficiencies, hormonal factors, and some environmental carcinogens (5). On the basis of the epidemiological observation that migrants tend to acquire the cancer rates of their new country, Doll and Peto concluded that differences in cancer rates can be attributed in part to environmental factors such as smoking, diet, and others.
On the basis of comparisons of high and low incidence countries, they concluded that 75–80% of cancers diagnosed in the United States in 1970 theoretically could have been avoided (2). Their highest estimates were for poor dietary habits (approximately 35%) and smoking (30%), as shown in Fig. 6 .
The question was what made the United States population different from low risk populations, at that time. The question why the US has higher cancer incidence rates than Greece, Japan, or Sweden is still not fully answered. The environmental factors that differ between these countries are many and include mainly lifelong dietary behaviors, physical inactivity, lifelong weight gain, alcohol consumption, and the use of tobacco.
Although the conclusion by Doll and Peto was provocative at that time, because of limited data from analytical and rigorously performed epidemiological studies, it is still true today, more than 25 years later.
Accumulated evidence from thousands of observational epidemiological studies have conﬁrmed the contribution of speciﬁc lifestyle factors to the etiology of cancer and have expanded the list of cancer risk factors to include also obesity and physical inactivity. The previously estimated 75–80% reduction in cancer burden was a theoretical maximum, and Doll and Peto acknowledged that it was rather unlikely that any society could change lifestyle enough – even over many years – to decrease cancer incidence by this amount. However, the new estimates indicate that more than 50% of all cancer
Fig. 6. Proportions of cancer attributed to nongenetic factors. Estimated proportions that could have been avoided in each category of factors as estimated by Doll and Peto (2).
cases could be prevented by achievable changes (6). Evidence indicates that in the United States (Fig. 7 ), obesity accounts for some 15% of all cancer cases, physical inactivity for 5% of cases, poor diet for 10–25% of cases, alcohol consumption for 4% of cancer cases, and tobacco use for 30% (7).
For the great majority of people who do not use tobacco, weight control, dietary choices, and the levels of physical activity are the most important modiﬁ able determinants of cancer risk (8–10). Although genetic factors inﬂuence the risk of cancer, most of the variations in cancer risk across populations and among individuals are due to factors that are not inherited (11,12). Such modiﬁ able lifestyle-related factors as no smoking, maintaining a health(Buy now from http://www.drugswell.com)y weight, staying physically active throughout life, and consuming a health(Buy now from http://www.drugswell.com)y diet can substantially reduce one’s lifetime risk for developing cancer (10,13). It is important to point out that the same health(Buy now from http://www.drugswell.com)y behaviors are also associated with reduced risk of developing cardiovascular disease.
As is shown in Figs. 3–5 , cancer rates especially for prostate and breast cancer, differ several fold between Western and Asian countries, similar to differences in food consumption (Fig. 8a – d ). Differences in food patterns between the four countries described in this chapter are large. In Greece there is much higher per capita availability of vegetables, roots and tubers, fruits, pulses, and nuts than in the three other countries (Fig. 8a , b ). In Sweden there is the highest per capita availability of milk and coffee (Fig. 8c , d ); Japan is leading regarding the per capita availability of ﬁsh and tea (Fig. 8 c, d), and USA is leading in red meat availability (Fig. 8c ).
Differences in prevalence of obesity between the four countries are several fold, with Japan having the lowest and USA the highest prevalence (Fig. 9 ). Overweight and obesity have reached epidemic proportions globally along with an adoption of a lifestyle characterized by a combination of excessive food intake and inadequate physical activity. The dramatic rise in prevalence of obesity and increasing inactivity has been accompanied by increases in the incidence and prevalence of type 2 diabetes. There is accumulating evidence that diabetes is associated with an increased risk for cancer at several sites (14).
Fig. 7. Proportion of cancer attributable to modiﬁable lifestyle factors in the United States according to recent estimates.
Roots and tubers
Fig. 8. (a) Time trends in mean per capita availability (in g/day) of selected food groups – cereals, roots and tubers, and vegetables – in Greece, Sweden, USA and Japan. ( b) Time trends in mean per capita availability (in g/day) of selected food groups – fruits and berries, pulses, and nuts – in Greece, Sweden, USA, and Japan. (c) Time trends in mean per capita availability (in g/day) of selected food groups – ﬁsh, red meat, and milk – in Greece, Sweden, USA, and Japan. ( d ) Time trends in mean per capita availability (in g/day) of selected food groups – coffee, tea and matè, and sugar crops – in Greece, Sweden, USA, and Japan.
Fig. 8. (continued)
Milk, whole, fresh
Fig. 8. (continued)
Food quantity/day/capita (g)
Fig. 8. (continued)
35 30 25 20 15 10 5 0
1980 1990 2000 2001
Fig. 9. Time trends in obesity prevalence among adult women and men in four countries from different geographic regions.
Differences in physical activity and inactivity between the countries described in this chapter are presented in Fig. 10 . As shown in Fig. 11a, b , temporal changes in decreasing physical activity between the 1930s and the 1990s among Swedish women and men are very striking in all age groups (16,17). Especially pronounced is the decreasing demand for occupational physical activity and decreasing energy expenditure related to walking.
Furthermore, there are differences between the four countries in alcohol consumption and tobacco use (Fig. 12 ). Temporal changes in these modiﬁable lifestyle factors that have been shown to be associated with cancer risk – namely food consumption patterns, obesity, physical inactivity, smoking and alcohol – are paralleled by changes in cancer incidence. Prevalence of smoking in Sweden and USA has been decreasing in both women and men (Fig. 12 ). Policy and community interventions have been especially successful in Swedish men.
This review on diet and cancer is limited to the three cancer sites with the highest incidence in developed countries.
Prostate cancer (PC) is the most frequent cancer among men in North America as well as in Northern and Western Europe. Causes of the disease are essentially unknown, although it is estimated in studies of twins that hereditability of PC is approximately
a Total physical activity -Women
Total physical activity -Men
(b) Temporal trends in speciﬁc types of physical activity among Swedish adolescent girls and boys, women and men.
42%, the highest of all studied cancers (11). There is approximately a 40-fold difference in the reported incidence and a 12-fold difference in mortality of PC between various geographic areas and populations (21). Diet is suspected to play a major role in the initiation, promotion, and progression of PC. Among the dietary factors that have
b Specific type of physical activity - Women
Specific type of physical activity - Men
Fig. 11. (continued)
most consistently been associated with increased risk of PC development are meat and milk products.
High consumption of meat, particularly red or processed meat, generally is associated with moderate to severe increases in risk of PC by 30 or more percent in most studies (22), although conﬂicting evidence exists (23). Those few studies that have separately analyzed the association, not only with total prostate cancer but also with advanced and metastatic tumors, have reported even higher risk estimates for the advanced stages of the disease (24). A two-fold increase was found for advanced cancer and a 2.2-fold increase in metastatic cancer compared with 40–50% increase for total PC. These results suggest a possible role of meat in the progression of PC. The mechanisms by which meat consumption might affect the risk of prostate cancer remain unknown. It has been speculated that the observed positive association may reﬂect the high intake of fat, especially that of total fat; in Asian countries with a low incidence of the disease, total intake of fat is much lower than in countries with high incidence, although ﬁ ndings of total dietary fat and speciﬁc fat types are mixed (24). Another speculation is that meat that is grilled or pan-fried at high temperatures contains heterocyclic amines that have been found to contain carcinogens in animal studies on rat prostates (25) . A recent prospective study has indeed shown that an average consumption of more than 10 g/ day of very well done meat, compared with no consumption at all, is associated with a statistically signiﬁcant 70% increased risk of incident prostate cancer (26). Red meat is a major source of zinc, which is known to be essential for testosterone synthesis (27). The use of zinc supplements of more than 100 mg/day and for more than 10 years was associated with more than two-fold increase in risk of PC compared with nonusers (28). High consumption of red meat and a high zinc and protein intake was also associated with a higher circulating concentration of insulin-like growth factor 1 (IGF-1) (29). Interestingly, high IGF-1 levels have consistently been associated with high incidence of PC (30).
Milk products also appear to consistently be associated with increased risk of PC. Those few studies that have analyzed advanced and metastasized PC separately suggested that the association might be stronger for the more advanced cancers than for all PC (22). This might indicate a possible role of dairy products in the progression of this neoplasm. The mechanisms behind these observed associations are not known. Many studies indicate that calcium, the main dietary component of dairy products, may play an important role in PC development. In the health(Buy now from http://www.drugswell.com) Professionals follow-up study, men who consumed more than 2,000 mg/day of calcium had an approximately ﬁ ve-fold increased risk of developing metastatic and fatal PC compared with those consuming less than 500 mg/day (31,32). High consumption of low-fat milk has been associated with a higher concentration of circulating IGF-1 (33). Another possibility is that branched fatty acids present mainly in milk fat, and also in beef, may up-regulate the a -methylacyl Co A racemase ( AMACR) gene, previously shown to be over-expressed in PC tumors, and not in health(Buy now from http://www.drugswell.com)y prostates (34).
There are also other dietary factors that are thought to be protective. Although there is a general health(Buy now from http://www.drugswell.com) recommendation to eat ﬁve or more servings of fruits and vegetables per day, the accumulated evidence does not support any reduced risk of prostate cancer (35). However, several epidemiological studies have reported that some vegetables, speciﬁcally tomatoes, and lycopene (the predominant carotenoid found in serum), from tomatoes mainly, are associated with lower risk of PC. Indeed, a review of four studies of serum lycopene and incidence of PC report a signiﬁcant reduction in risk (25–80%) (36). In a meta-analysis of 21 studies, high consumption of tomatoes resulted in a 10–20% risk reduction (37). There is also a suggestion that other carotenoids lower the risk (24). Several epidemiological studies have reported an inverse relationship with cruciferous vegetables (speciﬁcally cabbage, broccoli, cauliﬂower, and brussel-sprouts) and the risk of developing PC (24), whereas the European Prospective Investigation into Cancer (EPIC) did not (38). In the health(Buy now from http://www.drugswell.com) Professionals follow-up study, an inverse association was only observed for early stage cancer in younger men, suggesting that cruciferous vegetables may be important early on in the carcinogenesis process (39) . Anticarcinogenic phytochemicals that are present in cruciferous vegetables (indole-3-carbinol and isothiocyanates) can induce antioxidative enzymes and counteract oxidative damage. They have also been shown to have proapoptotic, antiproliferative, and antimetastatic properties in animal models of PC (40).
Furthermore, other phytochemicals found in fruits and vegetables, tea, and red wine, namely polyphenols and isoﬂavones, have been shown in experimental studies to have antioxidant, antiproliferative, antiangiogenesic, or proapoptotic effects (24,41) . Given the promising results from in vitro and animal studies on these phytochemicals, epidemiological studies are needed.
The most promising micronutrients regarding nutritional protective factors are vitamin E and selenium. Vitamin E, an antioxidant found mainly in vegetable oil, nuts and oils, has been observed to signiﬁcantly reduce the risk for PC among smokers in a Finnish intervention study (42). That study has shown that men receiving 50 mg/day of supplemental vitamin E (a-tocopherol) had a 30–40% reduction in PC incidence and mortality compared with men taking a placebo. Selenium is an essential micronutrient present mainly in grains, ﬁsh, and eggs. The level of selenium in the soil determines its level in the plants grown in that area. Therefore, any variation in the selenium levels of food may be largely derived from the levels of the geographic area in which they were grown. Selenium intake has been observed to predict a lower risk of PC in several large prospective studies, but this is not always the case (22,43). High vs. low selenium levels in nails or plasma resulted in a reduction of 50–65% in the risk of PC (44,45) . In the randomized Nutrition Prevention of Cancer Trial study, men taking supplemental selenium had a 50% lower risk compared with the placebo group (46).
In recent years, a great deal of attention has been given to the so-called phytoestrogens. These phytochemicals with some estrogen-like activities are present in plant foods. Most frequently studied are soy foods, but, Westerners traditionally consume other plant foods containing so-called lignans (sources of which include ﬂaxseed and rye), which are also ascribed estrogen-like and anticarcinogenic properties (47,48). In a recent large case-control study in Sweden, total or individual consumption of lignans or isoﬂ avonoids was not associated with PC. However, high total consumption of foods rich in lignans and isoﬂavones was associated with moderate decrease in risk of PC (49).
There are several studies showing that ﬁsh consumption decreases PC incidence and mortality (22,24,50). The mechanism behind this observation might be linked to marine omega-3 fatty acids, a source of which is oily ﬁsh (salmon, mackerel, sardines, and herring). Fish is also an additional source of selenium and vitamin D and is also considered to have anticarcinogenic properties (51). However, it has to be noted that the main source of vitamin D remains exposure to ultraviolet light.
Migration studies suggest that lifestyle, aside from genetics, is a key factor in breast cancer risk. Breast cancer rates are rising globally in patterns that correspond with lifestyle changes. Belief such as fatty foods cause breast cancer (52) while consumption of vegetables and fruit reduce this risk have not confirmed (53). Instead, obesity and disordered energy balance are proving to be important risk factors (54) . Indirect epidemiologic evidence suggests that diet in early life may matter most, possibly due to increased mammary sensibility to carcinogens (55). Adult diet composition may also play a role in breast neoplasia. Although dietary fat does not appear to influence breast cancer risk (52,56), carbohydrate quality intake may prove to be important. Even moderate alcohol consumption increases risk of breast cancer (57), yet this effect can be reduced by an adequate folate intake (58,59).
In the Pooling Project on Diet and Cancer analysis, which included over 7,000 cases of breast cancer, no association between total fat and risk of breast cancer was found (56). In recent analysis of the Nurses’ health(Buy now from http://www.drugswell.com) Study (NHS), a cohort of over 120,000 nurses, longtime exposure to dietary fat and the effect of time latency were examined (60). In this study which included over 3,500 postmenopausal women, there was no association between total fat intake and breast cancer, even after considering various disease latencies up to 20 years. An association was observed only for a very low and very high intake of fat (below 20% and above 50% of energy from fat) and when tumor type was considered. Monounsaturated fat has been associated with lower breast cancer risk in some studies (61,62), whereas animal fat has been associated with higher risk (63). However, there was no association observed between poly- or mono-saturated fat and breast cancer incidence in the Pooling Project (52,56) . Overall, substantial evidence demonstrates that adult consumption of fat does not increase the risk of breast cancer.
Carbohydrates and carbohydrate quality, as measured by glycemic index or glycemic load, have been positively associated with breast cancer risk in some case-control studies (64). Yet, no overall associations of carbohydrate or carbohydrate quality and breast cancer risk have been reported in prospective studies in adult diet. An inverse relationship of high ﬁ ber intake to postmenopausal breast cancer risk was noted in a Swedish prospective study (65), where the highest vs. the lowest quintile of ﬁber intake was associated with a signiﬁcant 42% lower risk. However, in most other prospective studies the associations between dietary ﬁber and breast cancer were null (64).
Alcohol consumption increases risk of breast cancer in a dose-response manner; each additional 10 g of alcohol consumed daily corresponds to a 9% (95% conﬁ dence interval 4–13%) increase in breast cancer risk, according to the Pooling Project results (57). In an updated analysis of the Nurses’ health(Buy now from http://www.drugswell.com) Study with over 5,300 cases, alcohol intake as low as half a drink daily was statistically signiﬁcantly associated with breast cancer risk (66). This association was observed with a variety of alcoholic beverages and drinking patterns. Estrogen levels increase signiﬁcantly with consumption of one to two alcoholic drinks daily (67), suggesting a potential mechanism through which alcohol may increase the risk of breast cancer. In a Swedish prospective cohort of over 1,200 cases of invasive breast cancer with known estrogen and progesterone receptor status, the association with alcohol seemed to be stronger for estrogen-positive breast cancer types (68). High intake of folic acid, which is involved in DNA-methylation and repair, has consistently been shown to minimize the excess risk of breast cancer associated with regular alcohol consumption (58). Analysis of plasma folic acid levels conﬁ rmed this mitigating effect, which is strongest in women who consume at least one drink daily (59). The public health(Buy now from http://www.drugswell.com) implications of this positive association between alcohol consumption and breast cancer are complicated by the protective effect of moderate alcohol consumption on cardiovascular disease and the overall reduction in total mortality (69) . Women who chose to consume alcohol regularly may beneﬁt from a multivitamin containing folic acid to lessen the risk of breast cancer (58).
Neither fruit nor vegetable consumption in adulthood seems to protect against overall breast cancer. The Pooling Project analysis showed no effect of adult consumption of fruit and vegetable consumption on breast cancer incidence (53). This lack of association was recently conﬁrmed in the EPIC cohort of ten European countries (70).
No association between total, red or white meat consumption, or dairy products and breast cancer was observed in the Pooling Project (71). Both calcium and vitamin D were inversely related to risk of postmenopausal breast cancer; dietary calcium and other components of dairy products were inversely related to risk of postmenopausal breast cancer, especially among women with estrogen-positive tumors (72) . Dietary intake and plasma levels of vitamin D were associated with lower risk of breast cancer in observational studies (73,74). In the Nurses’ health(Buy now from http://www.drugswell.com) Study, dietary carotenoids and total vitamin A were associated with lower breast cancer risk only among premenopausal women, especially in those who had a family history of breast cancer (75). However, no overall association between intake of carotenoids and breast cancer was shown in other prospective studies (64). In analysis of the Nurses’ health(Buy now from http://www.drugswell.com) Study cohort, a signiﬁ cant inverse association between high plasma levels of a-carotene, β-carotene, lutein and zeaxanthin, and total carotenoids and breast cancer risk was observed (76) . These data suggest that elevated serum carotenoids are associated with lower risk of breast cancer. Prospective studies have not found signiﬁcant overall associations between vitamin E, vitamin C, or selenium and breast cancer (64). Clarifying the role of diet in breast cancer etiology is important because there are few other factors to prevention. Obesity and disordered energy balance are proving to be important risk factors.
Colorectal cancer (CRC) is the third most common cancer among men and women combined in Sweden and the United States. Worldwide in 2002, approximately 1 million new cases of cancer were diagnosed (9.4% of new cases of cancer) and 529,000 individuals died from this malignancy (77). Incidence rates vary approximately 25-fold around the world, with the highest rates in Japan, North America, and Europe. The international differences and trends together with data from migrant studies imply that environmental factors play an important role in the etiology of CRC. The 25-fold geographic variation may be explained in large part by different dietary and other environmental factors.
There is considerable evidence that high consumption of red meat and processed meat may increase the risk of CRC (78). In a quantitative assessment of the association between red and processed meat consumption and CRC risk based on 15 prospective studies, there was an observed 28% increased risk in the highest relative to the lowest category of red meat consumption. Similarly, high vs. low processed meat consumption was associated with a 20% increase in CRC risk (79). Dose-response meta-analysis showed a statistically signiﬁ cant 31% increased CRC risk associated with each 120 g/day increment for red meat consumption, and the statistically signiﬁcant 11% increase in risk for each 30 g/day increment of processed meats (79). The mechanisms behind these associations may involve a combination of factors such as the content of fat, protein, and heme iron, and/ or meat preparation methods (for example, cooking in high temperature and preserving methods). The fat content of meat might inﬂuence the risk of CRC by increasing the production of secondary bile acids, which may promote colon carcinogenesis (80). However, epidemiologic studies have generally not shown a relation between fat intake and risk of CRC (81). Red meat contains higher amounts of heme iron than white meat (poultry and ﬁsh). Intake of heme iron was statistically signiﬁcantly positively associated with the risk of CRC in an American prospective study (82) and in the Swedish Mammography Cohort (83). Meta-analysis of prospective studies of poultry and chicken indicated a potential inverse association; comparing the highest to the lowest category of consumption a 12% decreased risk was indicated; there was no clear inverse association of CRC with ﬁsh consumption (84). The relationship between processed meat consumption and CRC may be partly due to N-nitroso-compounds (NOCs). An alternative mechanism through which red meat consumption might increase the risk of CRC is by increasing circulating insulin-like growth factor-1 levels. In a cross-sectional study of Swedish men, we found a statistically signiﬁcant positive relation between red meat consumption and serum IGF-1; men in the highest quintile of red meat intake had 13% higher serum IGF-1 levels than men in the lowest quintile (29).
There is accumulating evidence that dairy products are associated with lower risk of colorectal cancer. Dairy products are the major source of calcium and dietary vitamin D in Sweden (85) and in the United States (86); milk products are fortiﬁed with vitamin D in these countries. Milk products also contain other potentially anticarcinogenic compounds, including conjugated linoleic acid (CLA) and sphingolipids (87,88) . CLA has been shown to inhibit CRC cancerogenesis in animal models (89). In the Swedish Mammography Cohort, we observed statistically signiﬁcant inverse association between intakes of CLA and high-fat dairy foods (the main source of CLA) and risk of CRC (90). The relationship between milk consumption and risk of CRC was examined in the Pooling Project of Prospective Studies on Diet and Cancer in which the primary data from ten cohort studies (in ﬁve countries) were pooled (91). The pooled results revealed a statistically signiﬁcant inverse association between milk consumption and CRC ( P trend < 0.001); compared with individuals in the lowest category of milk consumption (<70 g/day), the multivariate relative risk for those in the highest category ( ³ 250 g/day) was statistically signiﬁcantly 15% lower. In the Cohort of Swedish Men, not included in the Pooling Project, men in the highest category of milk consumption (³ 1.5 glass/ day) had a statistically signiﬁcant 33% lower risk of CRC compared with those who consumed less than two glasses of milk per week (92). The inverse association between CRC and dairy products may be ascribed to calcium, vitamin D, CLA, sphingolipids, and other components of milk.
Studies that have examined circulating 25-hydroxy vitamin D [25(OH)D] serum concentrations and risk of colon and colorectal cancer have found reduced risk associated with higher vitamin D concentrations. Meta-analysis of these studies indicated that people in the highest category with the highest concentration of vitamin D had a signiﬁ cantly 54% lower risk of CRC in comparison to the lowest category (84). Meta-analysis of prospective studies based on intake of total vitamin D showed 21% statistically signiﬁ cantly decreased risk in those in the highest vs. the lowest category of intake (84).
Calcium has been hypothesized to reduce the risk of CRC by binding secondary bile acids and ionized fatty acids to form insoluble soaps in the colonic lumen, thereby diminishing the potentially proliferative stimulus of these compounds on colonic mucosa (93). Calcium may also directly inﬂuence the proliferative activity of the colonic mucosa and may also inﬂuence differentiation and apoptosis (94). Some clinical trials have shown that increased calcium intake could decrease colonic epithelial cell proliferation (95). Additionally, in randomized trials, calcium supplementation reduces the recurrence of colorectal adenoma (96,97) consistent with the role of calcium in the early stages of carcinogenesis. The totality of evidence from laboratory studies, observational epidemiological studies, and randomized trials of colorectal polyp recurrence supports the hypothesis that the high intake of calcium reduces the risk of CRC. In the Pooling Project of Prospective Studies of Diet and Cancer, where data from ten cohorts were analyzed together, the highest quintile when compared with the lowest quintile of dietary calcium intake was associated with a statistically signiﬁcant 14% lower risk and total calcium intake (including calcium supplements) with a 22% lower risk (91). In the Cohort of Swedish Men (not included in the Pooling Project), men in the highest quartile (>1,445 mg calcium/day) compared with those in the lowest quartile (<956 mg/ day) had a statistically signiﬁcant 32% lower risk (92).
Fruits and vegetables, besides being a rich source of dietary ﬁber, carotenoids, certain vitamins (particularly folate and vitamin C), and magnesium contain numerous phytochemicals that may have anticarcinogenic properties. Although the majority of about 30 case-control studies have found inverse associations between fruit and/or vegetable consumption and CRC risk, ﬁ ndings from prospective cohort studies have been less consistent (35). In a meta-analysis (98), the estimated relative risk for 100 g/day increase in fruit consumption was decreased by 7% in case-control studies (statistically signiﬁ cant) and by 4% in cohort studies (not reaching signiﬁcance). The corresponding risk for vegetable consumption was 13% in case-control studies (statistically signiﬁcant) and 4% (not signiﬁcant) in cohort studies. In summary, the hypothesis that high consumption of fruits and vegetables may reduce the risk of CRC has not been ﬁ rmly established.
The idea that a high ﬁ ber diet might reduce the risk of CRC dates back to the early 1970s, when Burkit postulated that the low occurrence of CRC he observed in Southern Africa was related to high ﬁber intake (99). Although the ﬁber hypothesis gained support from a number of case-control studies from different countries, the ﬁndings of cohort studies of dietary ﬁ ber intake in relation to risk of CRC have been inconsistent (100). Findings from large prospective cohort studies provide some indications that dietary ﬁber intake might be related in some way to risk of colon or rectal neoplasia; however, results are not entirely consistent.
A meta-analysis of 12 case-control studies showed a statistically signiﬁ cant 28% reduction in risk of CRC for high vs. low coffee consumption (32). However, recent results from large prospective cohort studies have not supported an association with coffee consumption (101,102). In a meta-analysis of epidemiologic studies (13 case-control and seven cohort studies) of tea drinking, there was no association with black tea and a statistically signiﬁ cant 18% lower risk for green tea (based on four case-control and four cohort studies); however, that inverse association was limited only to case-control studies (103). The accumulated evidence does not support an association of coffee or tea with risk of colorectal cancer.
Obesity is increasing at an alarming rate in the US, Europe, and all over the world, and the increase in childhood obesity is particularly troublesome (104). Lifestyle factors including diet, eating habits, levels of physical activity as well as inactivity are often adopted during the early years of life. As childhood obesity is also strongly related to obesity in adulthood, the best time to address the problem is early in life. Maintaining normal weight is challenging nowadays. On the one hand, there is an abundance of energy-rich foods that are often poor in nutrients, such as different types of fat-rich and sugar-rich cakes and other sweets. On the other hand, there are decreasing needs and opportunities for physical activity both at work and at leisure time. Such simple activity as walking has been decreasing during the past several decades, in parallel with increasing modernization (Fig. 11a – b ).
Even though people actually need less and less energy due to the increasing sedentary lifestyle, there has been a tendency for portion sizes to increase over time (105). The seriousness of these problems makes nutrition, physical inactivity, and obesity key priorities in the prevention of major chronic diseases including cancer.
In 2002, the IARC Prevention Report on Weight Control and Physical Activity concluded that obesity and lack of physical activity are major causes of cancer incidence and mortality (9). The accumulated evidence indicated that obesity was directly associated with risk of cancer at several organ sites including colon, breast (in postmenopausal women), endometrium, esophagus, and kidney (9). Furthermore, data from the American Cancer Society Cancer Prevention Study II, which followed more than 1 million men and women during 16 years, also showed direct associations between obesity and mortality from cancer of the prostate, pancreas, non-Hodgkin’s lymphoma, and myeloma (106). The conclusion from this large prospective study was that 16–20% of cancer deaths among American women and 14% of cancer deaths among men are attributable to obesity (107).
The IARC Prevention Report from 2002 also stated that there was accumulated sufﬁcient evidence to conclude that physical inactivity was linked to increased risk of breast and colon cancer (9). In a recent systematic review of 19 cohort studies and 29 case-control studies, it was reported that there was strong evidence for an inverse association between physical activity and postmenopausal breast cancer, but the evidence was much weaker for premenopausal breast cancer (108). In postmenopausal women, when comparing the highest with the lowest categories of physical activity, there were risk reductions ranging from 20 to 80%. In about half of the methodologically higher-quality studies, there was evidence for a dose-response relationship. Each additional 1 h of physical activity per week was associated with a 6% (95% conﬁ dence interval 3–8%) decrease in breast cancer risk. In a study of the California Teachers including over 110,000 women aged 20–79 years, strenuous long-term exercise activity was protective against invasive and in situ breast cancers. However, the protective effect was limited to estrogen receptor negative breast cancer (109).
We have recently reported that physical activity is also associated with decreased risk of endometrial cancer, especially among obese women (110). Interestingly, among diabetic women, who have two-fold increased risk, we observed that physical activity can reduce the risk to a similar level as among women without diabetes (111) . The mechanisms by which physical activity may protect against breast and endometrial cancer may involve body size, which affects estrogen exposure in postmenopausal women (112), and serum hormone levels (113). Furthermore, physical activity may inﬂ uence insulin sensitivity (114) and growth factors (115), as well as adiponectin (116) . Adiponectin has been shown to be associated with decreased risk of breast (117), endometrial, and other cancers (118).
Convincing epidemiological data support the role of physical activity in reducing colon cancer risk (9,119). Meta-analysis of prospective studies (published through October 2006) on leisure time physical activity and risk of colon cancer has shown statistically signiﬁcant 25% lower risk when comparing the highest to the lowest category (78). In contrast to colon cancer, there was no association between physical activity and risk of rectal cancer.
The American Cancer Society (ACS) publishes nutrition and physical activity guidelines to serve as a foundation for its communication policy and community strategies and ultimately to affect dietary and physical activity patterns among Americans. These guidelines, published every 5 years, represent the most current scientific evidence related to dietary and activity patterns and cancer risk. The recent guidelines were updated in October 2006. They are consistent with guidelines from the American Heart Association (120) and the American Diabetes Association (121) for the prevention of coronary heart disease and diabetes, as well as for general health(Buy now from http://www.drugswell.com) promotion, as defined by the Department of health(Buy now from http://www.drugswell.com) and Human Services’ 2005 Dietary Guidelines for Americans (122). In the ACS guidelines, it is very clearly stated that the most important modifiable determinants of cancer risk among those who do not use tobacco are weight control, health(Buy now from http://www.drugswell.com)y diet, and appropriate levels of physical activity. Evidence suggests that one third of cancers that occur in the USA each year can be attributed to diet and physical activity habits. health(Buy now from http://www.drugswell.com)y behavior such as maintaining health(Buy now from http://www.drugswell.com)y weight, staying physically active throughout life, and consuming a health(Buy now from http://www.drugswell.com)y diet can substantially reduce one’s lifetime risk of developing cancer (10,13). The same behaviors are also associated with decreased risk of developing cardiovascular disease. Recent ACS guidelines for cancer prevention are presented in Table 1 .
American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention, Updated in October 2006 (123)
Guidelines on nutrition and physical activity for cancer prevention
Maintain a health(Buy now from http://www.drugswell.com)y weight throughout life
Balance caloric intake with physical activity
Avoid excessive weight gain throughout the life cycle
Achieve and maintain a health(Buy now from http://www.drugswell.com)y weight if currently overweight or obese
Adopt a physically active lifestyle
Adults: engage in at least 30 min of moderate to vigorous physical activity, above usual activities, on 5 or more days of the week. Intentional physical activity is preferable for 45–60 min
Children and adolescents: engage in at least 60 min per day of moderate to vigorous physical activity at least 5 days per week
Consume a health(Buy now from http://www.drugswell.com)y diet with an emphasis on plant sources
Choose food and beverages in amounts that help achieve and maintain a health(Buy now from http://www.drugswell.com)y weight
Eat ﬁve or more servings of a variety of vegetables and fruits each day
Choose whole grains in preference to processed (reﬁ ned) grains
Limit consumption of processed and red meats
If you drink alcoholic beverages, limit consumption
Drink no more than one drink per day for women and two per day for men
The mission of the World Cancer Research Fund (WCRF) global network, an alliance of organizations dedicated to the prevention of cancer worldwide, is to raise awareness that the risk of cancer is reduced by health(Buy now from http://www.drugswell.com)y food and nutrition, physical activity, and weight management. WCRF supports research to develop and strengthen scientific knowledge of the relation of food and nutrition, physical activity, and weight management for cancer prevention.
The research and education programs of WCRF International and its national members are based on the conclusions and recommendations of the WCRF and American Institute for Cancer Research (AICR) Second Expert Report “Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective,” which was published in November 2007 (10). This report that summarized the accumulated knowledge on diet, physical activity, and cancer was distributed throughout the world and acclaimed as setting the agenda for the coming years on food, nutrition and lifestyle, and the prevention of cancer. Current recommendations in this Expert Report, based on meta-analysis and summaries of scientiﬁc articles, are presented in Table 2 .
It is essential to understand that the evidence used to formulate the WCRF global networks health(Buy now from http://www.drugswell.com) recommendations and research policy is based on the latest research investigation. It summarizes accumulated knowledge from about 10,000 scientiﬁ c articles.
World Cancer Research Fund and American Institute for Cancer Research, Guidelines for Cancer Prevention Through Diet and Physical Activity, 2007
Be as lean as possible within the normal range of body weight
Ensure that body weight through childhood and adolescent growth projects toward the lower end of the normal BMI range at age 21
Maintain body weight within the normal range from age 21
Avoid weight gain and increases in waist circumference throughout adulthood
Be physically active as a part of everyday life
Be moderately physically active, equivalent to brisk walking, for at least 30 min every day. As ﬁtness improves, aim for 60 min or more of moderate, or for 30 min or more of vigorous, physical activity every day
Limit sedentary habits such as watching television
Limit consumption of energy-dense foods and avoid sugary drinks
Consume energy-dense foods sparingly
Avoid sugary drinks
Consume “fast foods” sparingly, if at all
Eat mostly foods of plant origin
Eat at least ﬁve portions/servings (at least 400 g or 14 oz) of a variety of nonstarchy vegetables and of fruits every day
Limit intake of red meat and avoid processed meat
People who eat red meat from domesticated animals (beef, pork, lamb, goat) should consume less than 500 g (18 oz) a week, very little if any to be processed (meats preserved by smoking, curing or salting, or addition of chemical preservatives)
Limit alcoholic drinks
If alcoholic drinks are consumed, limit consumption to no more than two drinks a day for men and one drink a day for women
Limit consumption of salt and avoid mouldy cereals (grains) or pulses (legumes)
Avoid salt-preserved, salted or salty foods; preserve foods without using salt. Limit consumption of processed foods with added salt to ensure an intake of less than 6 g
(2.4 g sodium) a day. Do not eat cereals (grains) or pulses (legumes) that have mold Aim to meet nutritional needs through diet alone Dietary supplements are not recommended for cancer prevention Mothers should breastfeed; children should be breastfed Aim to breastfeed infants exclusively up to 6 months and continue with complementary
Cancer survivors should follow the recommendations for cancer prevention
All cancer survivors should receive nutritional care from an appropriately trained
professional. If able to do so, and unless otherwise advised, aim to follow the recommendations for diet, health(Buy now from http://www.drugswell.com)y weight, and physical activity
Interestingly, many aspects in the guidelines on nutrition for cancer prevention are very similar to dietary food patterns usually seen in Mediterranean basin countries, such as Greece, Italy, Spain, and France. The term “Mediterranean diet” reflects the dietary pattern characteristics of several Mediterranean countries during the early 1960s. Such patterns defined in the early 1990s are composed of (124):
Various aspects of the Mediterranean diet are considered favorable with regards to cancer risk. Studies have suggested that the cancer-conferring beneﬁts of this diet are due to not only high consumption of fruits, vegetable, whole grains, and ﬁsh but also olive oil (125,126). The Greek variant of the Mediterranean diet is especially interesting because Greeks have been in the area longer than other Mediterranean populations, and the early studies that pointed to the beneﬁcial effects of the Mediterranean diet were largely based in Greece (3). The diet of Crete is considered to represent the traditional diet of Greece prior to 1960 (127). Overall, the traditional Mediterranean diet may be thought of as having eight components:
A diet that has all of the characteristics described above has a score of eight, whereas a diet with none of these characteristics should have a score of zero. It has been reported that death rates were lower and life expectancy was longer among people scoring high on this dietary pattern compared with those with low scores (128,129).
In the Mediterranean diet, meals usually contain large quantities of whole-grain bread. Legumes and vegetables are consumed in large amounts in cooked dishes, soups, and salads are prepared with olive oil. Intake of milk is moderate, but consumption of cheese, and to a lesser extent yoghurt, is high; feta cheese is regularly added to most salads and vegetable stews. Meat, being expensive, used to be rarely consumed, whereas ﬁsh consumption was a function of proximity to the sea. Wine is consumed in moderation and almost always during meals (130). These characteristics of the Mediterranean diet are still well reﬂected in the per capita availability of foods in Greece in 1990s as shown in Fig. 8a–d . The most pronounced differences in consumed food amounts between Greece and Sweden, USA, and Japan are observed for vegetables, fruits, and berries, pulses, and nuts.
In summary, present American and WCRF guidelines on health(Buy now from http://www.drugswell.com)y diet for cancer prevention are remarkably in line with the dietary proﬁle of old Mediterranean traditions. A diet rich in plant foods and whole grain and low in foods of animal origin, accompanied by low to moderate alcohol consumption, should be actively promoted.
18 . Statistics, Sweden. National health(Buy now from http://www.drugswell.com) Interview Survey, 2006.
19. Time trends in smoking in the USA, 1980–2005. Atlanta, GA: Center for Disease Control and Prevention, 2006.
20 . WHO. Smoking in Greece and Japan. Geneva: WHO, 2006.
122 . US Department of health(Buy now from http://www.drugswell.com) and Human Services and US Department of Agriculture. Dietary guidelines for Americans. Washington, DC: US Government Printing Office, US Department of health(Buy now from http://www.drugswell.com) and Human Services, US Department of Agriculture, 2005.
Key Words: USDA Food Pyramids , Nutrition recommendations
1. HISTORY OF THE DIETARY GUIDELINES AND THE FOOD PYRAMIDS
Since 1894, the United States Department of Agriculture (USDA) has been providing the public with food guidance based on scientific evidence of food’s nutritional value. WO Atwater paved the way for the first USDA food guides with his research compiling food composition tables and determining nutritional requirements for the US population (1). The USDA released the first official food guide in 1916. Developed by Caroline Hunt, a nutrition specialist at the USDA, the guide placed food into five groups: milk and meat, cereals, vegetables and fruits, fats and fat foods, and sugars and sugary foods (2). Over time, food guides have been updated and revised as knowledge has changed, but the idea of selecting a variety of foods from different nutritional groups has been consistent since people usually eat a variety of foods. Among the most popular food guides was the “Basic Four.” Released in 1956, this guide divided food into four categories:
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_10, © Humana Press, a part of Springer Science + Business Media, LLC 2009
dairy, meat, grains, and fruit and vegetables. In 1979, a fifth group was added for fats, sweets, and alcohol (2), and this is generally how food has been characterized by the USDA since then.
In response to the public’s need for more comprehensive nutrition information, the USDA and DHHS released the ﬁ rst Dietary Guidelines for Americans booklet in1980. Developed to help individuals to choose and prepare foods for optimum health(Buy now from http://www.drugswell.com) and prevention of chronic disease, this new food guide offered more detailed information about how to select the most nutritious foods and the harm caused by the least nutritious, along with recommendations on how to maintain a health(Buy now from http://www.drugswell.com)y body weight (3) . The ﬁ rst Dietary Guidelines encouraged consumption of a variety of foods, including starch and ﬁber, along with avoidance of fats, sugars, and sodium. It also recommended moderation of alcoholic beverages.
After implementation of the new dietary guidelines, it was found that consumers and some professionals were largely unaware of its existence. Many thought that the USDA was still using the “Basic Four” (4). To remedy this, the USDA began research and development of a visual representation of the Dietary Guidelines in 1988. When designing the graph, the USDA stressed that it must convey variety, proportionality, moderation, and usability (4). Many potential designs, such as shopping carts, circles, and funnel shapes, were tested for their ability to express these ideas. The pyramid and a bowl shape were most successful, but the pyramid was chosen for its edge in communicating the ideas of proportionality and moderation (4). The resulting Food Guide Pyramid promoted a diet based heavily on bread, cereal, rice, and pasta (6–11 servings a day) and very low in fats and reﬁned sugars (5). It also recommended liberal consumption of fruits and vegetables, and two–three servings of meat and dairy a day. By this time, the differences between harmful saturated fats and beneﬁcial unsaturated fats were well known. Despite this, the government largely considered the American public unable to distinguish between different types of fat (6). Therefore, the Dietary Guidelines and corresponding Food Guide Pyramid offered no distinction between types of fat and promoted an overall low-fat diet in order to reduce consumption of saturated fats (6) (Fig. 1).
The release of the ﬁrst Food Guide Pyramid was met with both support and criticism. For most, the largest inadequacy of the ﬁrst Food Guide Pyramid was its simplicity. To many, it did not offer enough information to select the most nutritious foods within each food group. Some nutritional experts criticized its failure to distinguish between harmful animal fats and beneﬁcial vegetable oils (6–8), especially in light of the fact that the food guides of several nations, such as China, Australia, and Greece, address the use of different types of fat (6). Others worried that the public would be confused because the Food Guide Pyramid did not make a distinction between red meat and other apparently health(Buy now from http://www.drugswell.com)ier foods, such as poultry, ﬁsh, legumes, and eggs in the protein group (8) . The pyramid put an emphasis on consumption of breads, cereal products, and potatoes, though there was no evidence of a clear beneﬁt from this (8). Some thought it should be more speciﬁc about the consumption of whole grains leading to a decreased risk in heart disease rather than lumping all grains together in one recommendation (8) . The Pyramid was also criticized for lacking valuable information on physical activity and sodium and alcohol intake along with recommending confusing serving sizes that could lead to excess calorie consumption (6). Perhaps the only recommendation of the Food Guide Pyramid not to be disputed was increased consumption of fruit and vegetables.
Fats, Oils & Sweets Fat (naturally occuring and added)
Sugars (added) These symbols show fats and added sugars in foods.
Milk, Yogurt & Meat, Poultry, Fish, Dry Beans, Cheese Group Eggs & Nuts Group
Vegetable Group Fruit Group
Bread, Cereal, Rice & Pasta Group
Fig. 1. 1992 USDA Food Guide Pyramid.
Those who came to the Pyramid’s defense proposed that its core recommendations of variety, proportionality, and moderation are valid and that the obesity epidemic is a result of the public’s failure to follow these suggestions (9). Despite the criticism, over a decade elapsed before the USDA released a revised version of the Food Guide Pyramid.
In response to both widespread criticism and changing nutritional knowledge, the USDA released an updated version of the Food Guide Pyramid in 2005. As part of the revision it was renamed MyPyramid, to promote individuality in food choices, and was modernized with a companion website, http://www.mypyramid.gov. The new image itself contains very little information about each food group and no daily intake suggestions. It is intentionally vague, broadly representing the food groups and the recommendations of activity, moderation, personalization, proportionality, variety, and gradual improvement. The food groups are also now represented as vertical rather than horizontal bands on the pyramid. MyPyramid relies heavily on the website, MyPyramid. gov, and descriptive handouts to disseminate more detailed information about selecting foods and what quantities to eat. “Inside the Pyramid,” on MyPyramid.gov, contains detailed explanations about each group of foods and offers information on how to choose the most health(Buy now from http://www.drugswell.com)ful foods (Fig. 2 ).
In the information online, the 2005 Pyramid differentiates between different foods in the grain group, recommending that at least half of the public’s grain intake should be from whole grains. Like the earlier version, this new pyramid also encourages a low-fat diet, but advises the public to choose health(Buy now from http://www.drugswell.com)ier vegetable oils over solid animal fats.
Fig. 2. 2005 MyPyramid (adapted from www.mypyramid.gov ).
The 2005 Pyramid also offers more detailed recommendations in the meats and beans group, advocating for lean or low-fat meat choices and suggesting that ﬁsh, nuts, and seeds should be chosen over meat when possible. The revised Food Pyramid also improves upon its lack of information on physical activity and its previously confusing serving sizes. Exercise is now represented on the Pyramid and it recommends at least 30 min of physical activity a day. No longer does the Pyramid offer serving size suggestions for each group, instead the MyPyramid Plan on the MyPyramid.gov website calculates individualized serving needs based on gender, weight, age, and physical activity.
Another feature of MyPyramid.gov is the MyPyramidTracker. This online tool assesses the user’s dietary and physical activity and calculates his or her energy balance. It allows each individual to track their own adherence to the Food Pyramid guidelines and adjust their intake accordingly.
Although the new, interactive Pyramid has addressed many of the problems of its predecessor, it has still been the subject of some criticism. MyPyramid.gov offers a wealth of educational materials, but it is not readily available to underprivileged populations who are at high risk for many chronic diseases (10). Further research on the new Food Guide Pyramid should be conducted to determine if its recommendations are truly reaching the American public.
The USDA’s Food Guide Pyramid has undergone tremendous revision and now offers much more detailed recommendations, which are very similar to those of other nations, such as Japan and Canada (11). In the wake of the current obesity epidemic, it is essential that the American public stay informed and educated on which foods to choose, which to avoid, and what quantities they should eat. A graphic guide, such as the Food Guide Pyramid, makes this information much more accessible. In addition, the features now offered on the corresponding MyPyramid.gov website should give users all of the tools needed to follow the USDA’s Dietary Guidelines. The question that remains is whether the 2005 Food Guide Pyramid truly recommends the most effective diet for preventing chronic disease.
3. SCIENTIFIC EVIDENCE UNDERLYING THE CREATION OF MYPYRAMID
International comparisons have helped to shed light upon the effectiveness of various Food Pyramid recommendations in preventing chronic disease. Several studies comparing mortality and morbidity from coronary heart disease (CHD) among different countries have helped to elucidate the dietary factors involved. CHD mortality fell in USA and Australia in the 1960s, though it remained constant in England and Wales, which are comparable in demographics and quality of medical care (12). This drop in mortality was ultimately attributed to differences in fat consumption. Citizens of USA and Australia mostly switched from butter to margarine around 1960, and thus increased consumption of vegetable fat, while England and Wales did not begin the switch to margarine until 1973–1974 (12). In another study, a decline in mortality from heart disease in Poland in the 1990s was also related to a switch from animal to plant fats, along with increased fresh fruit and vegetable consumption (13). These findings, notwithstanding acknowledged limitations of ecological studies, support the beneficial nature of unsaturated plant fats over saturated animal fats.
In the Seven Countries Study, associations were found between the diets of certain regions and CHD. The two regions with diets lowest in saturated fat intake, Japan and the island of Crete in Greece, had the lowest mortality from ischemic heart disease. Concurrently, Finland had both the highest saturated fat intake and highest mortality from ischemic heart disease (14). Although the diets of the Japanese and Greeks in the study were both characterized by low saturated fat intake, the total fat intake of Greeks was over four times than that of the Japanese, mainly due to high consumption of olive oil (14) . These ﬁndings led to many more investigations into the beneﬁts of choosing vegetable oils over animal fats to prevent CHD.
Ecological studies have found several links between diet and various types of cancer too. Research comparing cancer incidence rates internationally found olive oil consumption to have a negative association with the development of colorectal cancer (15) . Several studies have found a connection between high intake of dietary fat (particularly animal fat) and certain cancers, as well as an inverse association between fruit and vegetable intake and cancer risk (16–19). Importantly, many of the associations between diet and cancer risk seen in ecological studies have been found to be weak or nonexistent when analyzed in prospective cohort studies or clinical trials, underlying the main drawback of ecological studies, that is uncontrolled confounding.
Many of the associations between dietary factors and chronic disease risk seen in ecological studies have also been validated by case-control studies. High-fat intake has been linked to various types of cancer, such as prostate, breast, and endometrial cancer (20–22), along with higher risk of cardiovascular disease (CVD) (23). Patients with severe nonalcoholic fatty liver disease (a condition related to the metabolic syndrome) had higher saturated fatty acid intakes (14% of daily energy) than age and BMI-matched controls (10% of daily energy) (24).
In accordance with ﬁndings from previous ecological studies, a study based in Greece found that individuals with a closer adherence to Mediterranean diet were at decreased risk for acute CVD (25). Higher consumption of vegetables has been connected to decreased risk of CVD (23), and in several case-control studies, high fruit and vegetable intake has been linked to decreased risk of pancreatic, lung, breast, ovarian, and rectal cancer (26–32). Risk for breast cancer and other cancers has been negatively associated with foods lower on the glycemic index, such as whole grains (33). Research on the correlation between dairy and meat intake and various cancers has been inconclusive, showing positive and negative association with cancer risk depending on the type. With the possible exception of the dairy recommendations, the USDA’s dietary guidelines seem to be consistent with most of these case-control studies.
Findings from cohort studies suggest that there is at least some relationship between adherence to the 1992 and 2005 Food Pyramid recommendations and reduced risk of chronic disease. Criticisms of the 1992 Food Guide Pyramid included whether it encouraged reasonable energy intake. A study of 4,994 men and women from the Third National health(Buy now from http://www.drugswell.com) and Nutrition Examination Survey found that participants who closely followed the 2005 Food Guide Pyramid consumed less calories than those who closely followed the1992 Food Guide Pyramid guidelines (34). Nutrient intakes were also improved for those who adhered to the 2005 Pyramid, with the exception of potassium and vitamin E. This information suggests that the 2005 Pyramid is improved in comparison to its earlier version in meeting nutritional needs while still constraining calories.
In 1995, the health(Buy now from http://www.drugswell.com)y Eating Index (HEI) was designed to measure adherence to USDA’s Dietary Guidelines, with higher scores corresponding to higher observance of the guidelines’ recommendations (35). This allowed researchers to begin assessing the effectiveness of the dietary guidelines in preventing chronic disease. Women among a cohort of the Nurses’ health(Buy now from http://www.drugswell.com) study whose HEI scores adhered closely to the Dietary Guidelines were not found to be at signiﬁ cantly lower risk for overall chronic disease after a 12-year follow-up period (36). They did, however, exhibit a small reduction in CVD risk. These ﬁ ndings were comparable with those from a cohort of men from the health(Buy now from http://www.drugswell.com) Professionals Follow-up Study, which found a weak inverse association between adherence to the Dietary Guidelines and overall risk for chronic disease (37) . Those men with the highest HEI score had a 28% lower risk of CVD, but no association was reported between HEI and cancer.
On the basis of these results, a new dietary index was developed called the Alternate health(Buy now from http://www.drugswell.com)y Eating Index (AHEI), which was found it to be a more reliable predictor of chronic disease risk (38). The predicted risk of CVD and overall chronic disease was lower for men and women with the highest AHEI scores. There was a much stronger inverse association between CVD and adherence to the Dietary Guidelines when using the AHEI (38).
To examine the relationship between adherence to the 2005 Dietary Guidelines and insulin resistance, a study was conducted in the Framingham Offspring Cohort measuring the association between fasting insulin resistance and a diet consistent with the 2005 Dietary Guidelines. There was a positive association between women with a close adherence to the 2005 Dietary Guidelines and insulin sensitivity; however, no such association was found among men (39). In prospective cohort studies, foods that are lower on the glycemic index improve insulin sensitivity and other risk factors for CVD (40–42). The 2005 Pyramid currently recommends making half of all grains consumed whole grains, which are lower on the glycemic index. This may account for the increased insulin sensitivity seen in individuals who adhere to the 2005 Dietary Guidelines.
Little relationship has been found between following the Food Pyramid and cancer risk. Instead, some recent cohort studies have investigated the relationship between adherence to certain food groups and risk of cancer. Among prospective cohort studies, results are mixed on the relationship between consumption of dairy and certain cancers. An analysis of ten cohort studies found an association between high-milk and -calcium intake and reduced colorectal cancer risk (43). Another prospective study among the health(Buy now from http://www.drugswell.com) Professionals Follow-up cohort found high-calcium intake to be associated with higher risk of advanced prostate cancer (44). Further analyses of cohort studies found no association either way between breast and ovarian cancer and dairy intake (45, 46). Thus, on the basis of current research, there seems to be little reason for the USDA to change their recommendations for three dairy servings per day until controlled trials are performed. Although ecological and case-control studies pointed to fruits and vegetables as important for cancer prevention, prospective cohort studies have shown little to no association between fruit and vegetable intake and cancer risk (47–51) . Although the latter study design offers the time sequence criterion for causality, neither one of these studies can prove causality. Thus, in order to truly determine the effectiveness of the Food Guide Pyramid and its corresponding food groups at reducing the risk of chronic disease, randomized trials must be performed.
The randomized trial is the only study design that can build on knowledge obtained and hypotheses generated by observational studies while at the same time is not plagued by the drawbacks of epidemiological studies. Few clinical trials to determine the Food Guide Pyramid’s effectiveness at preventing chronic disease have been completed. One trial conducted among active-duty Air Force members in a 90-day fitness program found that a group receiving individualized counseling using the Food Guide Pyramid had significant reductions in cardiovascular risk factors and an improved response to exercise training (52). Those using the Food Guide Pyramid experienced reduced energy from fat intake, BMI, total cholesterol levels, and LDL levels (52).
There is little information deriving from clinical trials speciﬁcally on the Food Guide Pyramid’s effectiveness in reducing chronic disease. In addition, several other diets have been shown to be beneﬁcial, especially in reducing CVD outcomes, and may thus inform future dietary recommendations. A meta-analysis of 27 clinical trials suggests that replacing saturated fats with polyunsaturated fats is more beneﬁcial than replacing them with either carbohydrates or monounsaturated fats (53). In one trial, patients with a recent acute myocardial infarction (MI) were instructed to eat a low-fat diet, and an intervention group was also advised to eat more fruits, vegetables, nuts, and grain products. The early initiation of the intervention (within 72 h of MI) resulted in a signiﬁ cant decrease in cardiac events for the intervention group after a 1-year follow-up (54). The group eating a diet high in ﬁber, vitamins, and minerals also resulted in signiﬁ cant decreases in blood lipoprotein levels and fasting blood glucose.
Another trial found that mortality was reduced by about 29% in a 2-year follow-up of patients recovering from an MI who increased their intake of fatty ﬁsh and ﬁ sh oil (55). In this same study, however, there was no evidence of beneﬁt from increased ﬁ ber or decreased fat. Randomized trials have also shown that a diet high in monounsaturated fatty acids, such as those found in nuts, is more favorable than a low-fat diet, since it lowers LDL cholesterol but not HDL cholesterol (56, 57). Diets that replace saturated fatty acids with polyunsaturated fatty acids can reduce LDL cholesterol by 9.8% (58).
Improved health(Buy now from http://www.drugswell.com) outcomes have historically been associated with the diet followed by the Mediterranean region of the world. This diet pattern is generally defined by large intakes of whole grains and plant foods, olive oil as the major fat, low-to-moderate intakes of dairy, fish, and poultry, low intake of red meat, and low-to-moderate consumption of wine (59). The Lyon Diet Heart Study performed a randomized trial to elucidate whether a Mediterranean-type diet might reduce the occurrence of cardiovascular outcomes in patients who have had an MI. After a 4-year follow-up, the final report confirmed the protective effects of the Mediterranean diet (60). This diet may also be beneficial in prevention of the metabolic syndrome which is associated with type 2 diabetes and CVD (61). Patients with the metabolic syndrome following a Mediterranean-style diet for 2 years benefited from a reduction in inflammatory markers, decreased insulin resistance, and improved endothelial function (61). In addition, a Mediterranean-style diet has been shown to be associated with higher adherence rates than low-fat diets of the same calorie intake, resulting in health(Buy now from http://www.drugswell.com)ier body weight (62).
The beneﬁts of the Mediterranean-type diet may be related to inclusion of whole grains over reﬁned carbohydrates, moderate alcohol intake, as well as prudent use of nuts, especially walnuts. Several randomized trials have proven the beneﬁts of whole grains in decreasing risk of heart disease, such as improving insulin sensitivity and lowering LDL cholesterol concentrations (42). Moderate alcohol consumption has also been shown to improve insulin sensitivity, lower blood pressure, and reduce the risk of CVD, such as ischemic stroke (63–66). A daily serving of 30 g of walnuts, which have higher polyunsaturated fat content than other nuts, increased HDL to total cholesterol ratio in patients with type 2 diabetes (67). In addition, walnuts have been shown to improve endothelial function (67, 68). We have recently shown that the combination of these food items in the context of the Mediterranean diet increases the circulating levels of adiponectin, an adipocyte secreted hormone which acts as an endogenous insulin sensitizer. Adiponectin can in turn improve insulin resistance, optimize glycemic control, and decrease lipid levels and inﬂ ammatory markers.
Clinical trials hoping to determine the effects of diet on cancer risk have been less conclusive. In the Women’s health(Buy now from http://www.drugswell.com)y Eating and Living randomized trial among women previously treated for breast cancer, an intervention group eating a diet low in fat and very high in vegetables, fruits, and ﬁber did not have a reduction in breast cancer events or mortality in a 7.3-year follow-up period (69). Many of the dietary factors associated with cancer in case-control and observational ecological studies have not been replicated in controlled trials, making it difﬁcult to make nutritional recommendations solely on the basis of cancer prevention. Obesity is a risk factor for many types of cancer, however, so diets effective in obesity prevention should be followed.
On the basis of current scientific evidence, the nutritional guidelines put forth by the USDA are reasonable for most health(Buy now from http://www.drugswell.com)y Americans. Several prospective cohort studies and one controlled trial have shown that closer adherence to the dietary guidelines provides at least some benefit in preventing chronic disease. However, more specificity is necessary so that the public may truly choose the health(Buy now from http://www.drugswell.com)iest foods from each food group. Importantly, more clinical trials are needed to conclusively demonstrate the efficacy and cost-effectiveness of not only the guidelines in general but also the individual recommendations more specifically.
Certain areas of uncertainty and/or areas where the recommendations of MyPyramid can be improved remain. MyPyramid’s recommendation to make “half your grains whole” has been proposed to be a step in the right direction. On the basis of overwhelming scientiﬁc evidence on the beneﬁts of choosing whole grains over reﬁ ned carbohydrates in preventing type 2 diabetes and CVD and the readily available array of whole grain products now offered, it seems reasonable to recommend that Americans make all of their grains whole whenever possible for the optimum prevention of heart disease.
High fruit and vegetable intake does not seem to have the preventative powers for cancer that researchers once thought. Diets rich in fruits and vegetables still appear to be beneﬁcial for the prevention of CVD and further investigations must be performed to determine which diets are most beneﬁcial for cancer prevention. Fruits and vegetables are still a source of many essential vitamins and nutrients for overall health(Buy now from http://www.drugswell.com), however, and when added to a diet that previously lacked them, fruits and vegetables will likely take the place of other less nutritious foods. Further clinical trials are needed to fully substantiate these recommendations, though.
Although some associations have been made in cohort studies between dairy products and cancer risk, the relationship is still largely inconclusive. Given currently available evidence in conjunction with the beneﬁcial effect of low-fat dairy products in obesity and metabolism, there seems to be no fault in recommending low-fat and fat-free dairy products at this time. Thus, future clinical trials must determine whether people at risk for certain cancers should be advised to lower dairy consumption, and controlled trials should be performed to determine what the effect of dairy products is on cancer outcomes as well as obesity, diabetes, and the metabolic syndrome.
Several authors have suggested that MyPyramid should be more authoritative in its advice on protein. Clinical evidence touts the beneﬁts of fatty ﬁsh and nuts in the prevention of CVD, type 2 diabetes, and the metabolic syndrome. Since nuts, such as walnuts, are so useful in improving blood cholesterol proﬁles, it has been suggested that the USDA should recommend that one serving of protein a day be from nuts, and speciﬁcally walnuts, but again more clinical trials are also needed in this area. In a health(Buy now from http://www.drugswell.com)y diet, it is believed that red meat should be eaten very sparingly, and replaced by lean poultry and ﬁsh, as is done in the Mediterranean-type diet. In this area, it has been suggested that the Food Pyramid does not provide enough information to guide the public to the health(Buy now from http://www.drugswell.com)iest possible diet.
Clinical trials have consistently shown that a low-fat diet may not be as beneﬁ cial as a diet that replaces saturated fatty acids with mono- and polyunsaturated fatty acids. For example, the success of the Mediterranean diet in improving cardiovascular outcomes has been largely attributed to replacing animal fats with olive oil. In addition, diets, such as the Mediterranean, that replace saturated fats with these health(Buy now from http://www.drugswell.com)ier fats are more palatable than low-fat diets and have higher adherence rates, resulting in more sustained weight loss and health(Buy now from http://www.drugswell.com) beneﬁts. After over a decade of advising Americans to avoid fat, several experts believe that the USDA needs to provide more information to change the public perception of fat (6, 7). More detailed information, and thus more detailed clinical studies on the beneﬁts of replacing animal fats and saturated fats with olive oil, monounsaturated fats, and polyunsaturated fats are clearly needed.
Last but not least, in a nation where over half of adults are overweight or obese, there is no question that authoritative dietary recommendations are necessary to educate Americans on the health(Buy now from http://www.drugswell.com)iest food choices. The USDA’s dietary guidelines and corresponding Food Pyramids are useful in this regard, but several experts agree that these must be more discriminating in their advice on total energy intakes, grains, proteins, and fats based on current scientiﬁc evidence. Alternative pyramids have been proposed, such as Walter Willett’s health(Buy now from http://www.drugswell.com)y Eating Pyramid, that separate reﬁned carbohydrates from whole grains and red meat and animal fats from leaner, more nutritious proteins.
Finally, another criticism by many experts is that the USDA’s decision to put the more detailed information on each food group online fails to recognize the signiﬁ cant portion of the US population without home internet access. Without the additional information provided online, the 2005 pyramid is nothing more than a triangle that lists the different food groups, leaving no way for users to choose the health(Buy now from http://www.drugswell.com)iest foods in each group. A more effective way of distributing this information must be considered so that a large percentage of Americans, especially the underprivileged ones who tend to be more prone to consume a less health(Buy now from http://www.drugswell.com)y diet, are not left in the dark on the ﬁner points of the USDA’s nutritional guidelines.
In summary, although the 2005 MyPyramid appears to be a welcome advance in relation to previously available guidelines, much more is needed in terms of research to support dietary recommendations as well as public health(Buy now from http://www.drugswell.com) efforts to best disseminate the message on a diet that can prevent and/or improve adverse health(Buy now from http://www.drugswell.com) outcomes.
Key Words: Diet , Dietary , Nutrition , Guidelines , Heart disease , Chronic disease
In 1992, the United States Department of Agriculture (USDA) officially released its first Food Guide Pyramid, which was intended to help the American public make food choices that would maintain general good health(Buy now from http://www.drugswell.com) and reduce risk of chronic disease (Fig. 1 ).
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_11, © Humana Press, a part of Springer Science + Business Media, LLC 2009
Many other countries followed this lead; for example, the Iranian food guide pyramid was a direct translation. The core message of the USDA pyramid was resoundingly low fat: all fats and oils were to be consumed sparingly and, as replacement, “complex carbohydrates” were to be consumed in abundance, 6–11 servings a day. Generous amounts of vegetables (including more complex carbohydrates as potatoes), fruit, and dairy products were encouraged, and at least three servings per day from the “meat” group were advised, consisting of red meat, poultry, nuts, legumes, and eggs. Even at the time when the pyramid was first released, we had long known that some types of fat are essential, and that polyunsaturated fat could reduce plasma total cholesterol and incidence of coronary heart disease. In contrast, there was little evidence that high intake of starch is beneficial. Since 1992, evidence has continued to mount that the USDA pyramid provided misleading guidance to those seeking health(Buy now from http://www.drugswell.com)y food choices.
How did the pyramid go so wrong? Facing an epidemic of high cholesterol and coronary heart disease, and knowing that dietary saturated fats raise blood levels of cholesterol, policy makers sought to reduce dietary saturated fat. Apparently, however, it was considered too difﬁcult to educate the public about the subtleties of types of fat. Instead, the thinking went, since saturated fat represented such a large fraction of dietary fat, if we advocate low fat, saturated fat intake would drop. Also, in the early 1980s, based largely on comparisons between countries, the belief developed that total fat in the diet was the primary factor underlying the high rates of breast, colon, and prostate cancer in Western counties. This led to a clear, simple message that fat is bad. Because protein in the diet is relatively constant (and often associated with saturated fat), the notion that fat is bad led to the corollary that carbohydrates are good, even without direct evidence. At the time the pyramid was developed, the typical US diet contained about 40% of calories from fat. It was thought that with a concerted campaign, we might have 30% as a reasonable goal. This led to the widespread adoption of 30% of calories from fat as a limit. The 30% limit became so entrenched in dietary guidelines in the US, and many other countries that even the sophisticated observer could be forgiven for thinking that there must be many studies showing that individuals with that level of fat intake enjoyed better health(Buy now from http://www.drugswell.com) than those with higher levels. In fact, there were no such studies at all.
The concept that fat in general is to be avoided derives largely from observations that affluent Western countries have both high intakes of fat and high rates of coronary heart disease. However, this correlation was limited to saturated fat, and countries with high intake of monounsaturated fat tended to have lower rates. In the seminal study conducted by Keys and colleagues, the two regions with the lowest rates of heart disease were those following the traditional diets of Japan, with about 8–10% of calories from fat, and the traditional diet of Crete, with approximately 40% calories from fat (Fig. 2 ). International comparisons need to be interpreted cautiously, nevertheless, because many factors, such as smoking rates, physical inactivity, and adiposity, are also correlated with western affluence.
Evidence from early controlled feeding studies in the 1960s documented the adverse effects of saturated fat on total serum cholesterol levels, which are associated with higher risk of coronary heart disease, but also showed that polyunsaturated fat reduces serum cholesterol. Thus, dietary advice during the 1960s and 1970s emphasized replacement of saturated fat with polyunsaturated fat, not total fat reduction. The subsequent doubling of polyunsaturated fat consumption in the US probably contributed greatly to the halving of coronary heart disease rates in the US (1). For reasons described earlier, in the 1980s dietary advice subtly shifted to replacing fat in general with carbohydrate, which is the foundation of the USDA pyramid. The wisdom of this direction became questionable with the appreciation that total serum cholesterol can be subdivided: the LDL fraction increases but the HDL fraction reduces risk of coronary disease. More recently, serum triglyceride levels have also been associated with higher risk. Controlled feeding studies have shown that when saturated fat is replaced by carbohydrate, total and LDL cholesterol levels do fall, but HDL also falls proportionally, and triglyceride levels rise (2) . Thus, the ratio of LDL or total cholesterol to HDL does not change, which would predict little reduction in heart disease risk. Replacing either poly or monounsaturated fat with carbohydrate would actually make the serum cholesterol ratio worse, but replacing saturated
Y = 10-YEAR CORONARY INCIDENCE PER 10,000 MEN
X = % DIET CALORIES FROM TOTAL FATS
Ten-year incidence rate of coronary heart disease, by any diagnostic criterion, plotted against the percentage of dietary calories supplied by total fats.
Fig. 2. Ten-year incidence of coronary heart disease, by any diagnostic criterion, plotted against the percentage of dietary calories supplied by total fats (Keys, 1980).
fat with either polyunsaturated or monounsaturated fat improves this ratio and would be expected to reduce heart disease. The relation of dietary fat to heart disease became more complicated with the appreciation that trans-unsaturated fatty acids (produced by the partial hydrogenation of liquid vegetable oils) have important biological effects. Trans fats have uniquely adverse characteristics because they raise serum LDL and triglycerides and reduce HDL (3).
Although the effects of diet on blood cholesterol fractions and triglycerides are important, we now know that dietary factors can inﬂuence many other pathways that are important in the cause and prevention of coronary heart disease (Fig. 3 , multiple pathways) (4). For example, omega-3 fatty acids (from ﬁsh and some plant oils) can reduce the likelihood of ventricular ﬁbrillation (and therefore sudden cardiac death), and there is now solid evidence that trans fats also increase inﬂammatory factors (5,6), which appear to increase risks of cardiovascular disease and type 2 diabetes. Thus, it is also important to assess directly the relation of diet to heart disease incidence because this will integrate all the adverse and beneﬁcial effects of a dietary factor. Ideally, studies of diet and heart disease would be conducted as trials in which individuals are randomly assigned to one diet or another and followed for many years. Because of practical constraints and cost, few such studies have been conducted, and most of these have been in patients with existing heart disease. Although limited, these studies have supported beneﬁts of replacing saturated fat with polyunsaturated fat, but not with carbohydrate (7). The best alternative is usually to conduct large prospective observational studies in which the diets of many persons are assessed periodically over time and participants are
Fig. 3. Pathways leading from diet to incidence of coronary heart disease (CHD).
monitored for the development of heart disease and other conditions. In these studies, smoking, physical activity, and other potential risk factors can be measured and accounted for in the analysis. Thus, we have followed nearly 90,000 women who ﬁ rst completed detailed questionnaires on diet in 1980 and over 50,000 men who were enrolled in 1989. After adjusting for smoking, physical activity, and other recognized risk factors, we found strong relationships between type of dietary fat and risk of heart disease in the direction predicted by the controlled feeding studies. Speciﬁcally, compared with the same percentage of energy from carbohydrate, intake of trans fats was strongly associated with greater risk of coronary heart disease, saturated fat was only weakly related to risk, and both monounsaturated and polyunsaturated fats were associated with lower risk (8). Because of the opposing relationships for speciﬁc types of fat, the percentage of calories from total fat was not associated with risk of heart disease. This adds further support to the conclusion of a report by the National Academy of Sciences in 1989 that total fat intake per se is not a determinant of coronary heart disease (9). Although the relation of intake of trans fat to risk of coronary heart disease was initially controversial, this has been reproduced multiple times (5).
As for coronary heart disease, the belief that dietary fat is a major cause of cancer was derived largely from correlations among countries between per capita intake of total and animal fat and rates of cancers common in affluent countries, including cancers of the breast, colon, and prostate. However, in large prospective studies in which confounding variables could be better controlled, there has consistently been little relation between intakes of total and specific types of fat during mid life and risks of cancers of the breast and colon (10). Data on diet and prostate cancer remain limited, but some studies have suggested positive associations with animal fat. Thus, it is reasonable to make decisions about dietary fat primarily on the basis of its effects on cardiovascular disease, not cancer.
Excess body fat, including both mild overweight and obesity, is the most important nutritional problem in the US and an increasing number of countries, because it is a major risk factor for many diseases including type 2 diabetes, coronary heart disease, cancers of the breast, colon, kidney, esophagus, and endometrium, osteoarthritis, cataracts, and many other conditions. Dietary fat has been believed to be an important contributor to overweight because it contains more calories per gram and also it may be more efficiently stored as fat than carbohydrate. However, it is now clear that any differences in metabolic efficiency are not practically important and that the balance of total calories rather than just fat calories are important in weight control (11). Thus, the critical issue is whether the fat composition of the diet influences our ability to control caloric intake, and theories abound why one diet should be better than another. Long-term empirical data are essential, but remarkably sparse. In randomized trials, individuals assigned to low fat diets often tend to loose a few pounds during the first months, but then regain their weight. In randomized trials lasting a year or longer, there has consistently been no greater weight loss with low fat diets (11,12).
Because adequate caloric intake is essential, a substantial reduction in dietary fat practically implies an increase in carbohydrate. Because of concerns about consumption of “empty calories” from sugar, high intake of “complex carbohydrates,” mainly starch in the form of bread, rice, pasta and crackers, formed the base of the 1992 USDA pyramid. However, refined carbohydrates, such as white bread and white rice, are rapidly metabolized to simple sugars and cause a greater rise in blood glucose and insulin levels than grains that have not been milled into fine flour. In addition to producing a rapidly absorbed form of starch, the refining process also removes many vitamins and minerals and fiber. Indeed, potatoes raise blood sugar levels more rapidly than the same amount of calories from table sugar. The rapid rise in blood sugar stimulates insulin release, and a consequent sharp decline in blood sugar, sometimes even going below baseline. These sharp swings in glucose and insulin have deleterious metabolic consequences, raising triglycerides, and lowering HDL. The precipitous decline in glucose can also lead to more hunger after a carbohydrate rich meal, and may contribute to overeating and obesity. Thus, the concept of “complex carbohydrates” is not based on sound physiological principles. A different way to classify carbohydrates is by their propensity to raise blood sugar levels. Foods have a specific glycemic index, reflecting this propensity compared with a standard. The glycemic index depends not only on the chemical composition, but also on the physical form of the food (13). The glycemic load takes into account both the glycemic index of the food, and the amount of carbohydrate. In our large prospective studies, we have found that high intake of starches from refined grains and potatoes (i.e., a high glycemic load) is associated with higher risk of type 2 diabetes and coronary heart disease, and that greater intake of cereal fiber is related to lower risk of these conditions (14,15).
As noted earlier, replacement of dietary fat with carbohydrate creates the adverse metabolic picture of low serum HDL and high triglycerides. Recent evidence also indicates that this adverse metabolic response to carbohydrate is substantially worse among persons who already have a greater degree of insulin resistance, mainly as the result of overweight and inactivity (16–19). This can account for the ability of traditional farmers in Asia and elsewhere, who have been extremely lean and active, to consume large amounts of carbohydrate without experiencing diabetes or heart disease, whereas the same diet in a more sedentary population can have deleterious effects.
High intake of fruits and vegetables is perhaps the least controversial aspect of the dietary pyramid, and reduction in cancer risk has been a widely promoted benefit. However, most of the evidence for a cancer benefit has come from case–control studies, in which patients with cancer and selected control subjects are asked about their earlier diets. These retrospective studies are susceptible to numerous biases, and recent findings from large prospective studies have tended to show little relation between overall fruit and vegetable consumption and cancer incidence (20). Although some benefits probably exist for specific components of some fruits and vegetables and risks, the benefit of a general increase in fruit and vegetable consumption has probably been overstated. One component that does seem to be beneficial for reducing risk of colon and possibly other cancers is folic acid, but vitamin supplements and fortified foods are the major source of this vitamin in the US.
Although the beneﬁts of fruits and vegetables for cancer prevention are probably small, substantial evidence from cohort studies indicates that higher intake will reduce risks of cardiovascular disease (20) . This beneﬁt is probably due to many constituents, but folic acid and potassium appear to be contributing factors. Inadequate folic acid is also responsible for higher risks of serious birth defects, and low intake of lutein, a pigment in green leafy vegetables, has been associated with greater risks of cataracts and degeneration of the retina. Thus, there are many reasons, besides being a primary source of many vitamins needed for good health(Buy now from http://www.drugswell.com), to consume the recommended ﬁ ve servings per day of fruits and vegetables, even if this has little impact on cancer risk. However, the inclusion of potatoes as a vegetable in the USDA pyramid had little justiﬁ cation as they are mainly consumed as a source of starch and do not contribute to the beneﬁ ts seen for other vegetables. Not surprisingly, we have found that greater intake of potatoes was associated with higher risk of type 2 diabetes (21).
Low carbohydrate diets have been popular for weight control, although the long-term effects on weight are not clear, and concerns have been raised that these diets might increase risks of heart disease because they are often high in saturated fat and cholesterol. However, within the Nurses’ health(Buy now from http://www.drugswell.com) Study (22) we found that low carbohydrate diets were not associated with risk of coronary heart disease, probably because the reduction in glycemic load balanced the higher intakes of saturated fat and cholesterol. When the sources of fat and protein were mainly from vegetable sources, we found that a reduced carbohydrate intake was associated with a lower risk of heart disease.
Although treated equally by the USDA pyramid, the health(Buy now from http://www.drugswell.com) consequences of consuming red meat, poultry, fish, legumes, nuts, and eggs are quite different. High consumption of red meat has been associated with increased risk of coronary heart disease, probably because of its content of saturated fat and cholesterol, and higher risk of type 2 diabetes and cancers of the colon and possible prostate. The elevated risk of colon cancer does not seem to be due to the fat content of red meat; processed meats may be particularly related to this cancer. In contrast, the fat in poultry and fish is more unsaturated than that in red meat, and fish is an important source of the essential omega-3 fatty acids. Not surprisingly, we have seen that those who replace red meat with chicken and fish have a lower risk of coronary heart disease and colon cancer. Eggs are high in cholesterol, but consumption up to one per day does not appear to have adverse effects on heart disease risk (except among diabetics), probably because the effects of a slightly higher cholesterol level are counter balanced by other nutritional benefits. Many people have avoided nuts because of their high fat content, but the fat in nuts, including peanuts, is mainly unsaturated, and walnuts in particular are a good source of omega-3 fatty acids. In controlled feeding studies, nuts improve blood cholesterol fractions, and in multiple cohort studies those who consume more nuts have lower risks of heart disease. Thus, treating these various sources of proteins as equals fails to provide the public with information needed for health(Buy now from http://www.drugswell.com)y choices.
8. DAIRY FOODS
The USDA pyramid promoted high consumption of dairy products, which has usually been justified by their high content of calcium and the prevention of osteoporosis and fractures. Although the highest rates of fractures are found in countries with high dairy food consumption, large prospective studies have consistently not shown a lower risk of fractures among those with high intake of dairy products and thus more studies are needed (23). Calcium is an essential nutrient, but the US adequate intake of calcium for bone health(Buy now from http://www.drugswell.com) (1,200 mg/day for persons over 50 years of age) has probably been overstated by reliance on short-term studies, whereas British and other EU countries’ adequate intakes range between 700 and 800 mg/day. If a person needs more calcium, this can also be obtained at lower cost and without saturated fat or calories by taking a supplement. Several lines of evidence now suggest that low calcium intake can modestly increase risk of colon cancer (24), but most of the benefit of higher intake appears to be achieved by a good overall diet plus the equivalent of about one or two glasses of milk, or one or two portions of dairy products per day, which would correspond approximately to the UK definition of adequate intake of about 700 mg/day.
Higher than the recommended (see below) consumption of dairy products cannot a priori be assumed to be safe and effective because we are only now beginning to have the data to evaluate the consequences of high intake throughout life. In several studies, despite lower risk for colon cancer, men who consume high amounts of calcium or dairy products have experienced increased risk of prostate cancer (25) and in some cohort studies women with high intakes have had higher rates of ovarian cancer. Although fat was initially assumed to be the responsible factor, this has not been supported in more detailed analyses; high calcium intake itself seemed most clearly related to risk of prostate cancer. In contrast, low calcium intake is related to risk for colon cancer. The role of calcium, vitamin D, and dairy products in health(Buy now from http://www.drugswell.com) and disease is thus an area in need of more research. At the moment, the authors consider it imprudent to recommend more than two servings per day.
9. THE OVERALL IMPACT OF FOLLOWING THE USDA FOOD PYRAMID
With strong support from many elements of the food industry, the USDA food guide pyramid became a highly recognized icon. Many studies have assessed how well its message was adopted by the American public, but few studies have evaluated the health(Buy now from http://www.drugswell.com) of individuals who followed those guidelines, compared with others. Some benefits seem likely: by decreasing total fat intake consumption of saturated and trans fat will be reduced, and fruits and vegetables will be increased. However, the pyramid could also have led people to reduce desirable unsaturated fats and to increase consumption of refined starches, so that the benefits might be counterbalanced by harm.
To evaluate the overall impact of following the Pyramid message, we used the health(Buy now from http://www.drugswell.com)y Eating Index (HEI), a score developed by the USDA, to measure adherence to the Pyramid and its accompanying dietary guidelines in federal nutrition programs. From the data collected in our large cohort studies, we calculated each participant’s health(Buy now from http://www.drugswell.com)y Eating Index score and then examined the relation of these scores to subsequent risk of major chronic disease, deﬁned as any heart attack, stroke, cancer, or nontraumatic death from any cause (25–27). In analyses adjusted only for age, women and men with the highest health(Buy now from http://www.drugswell.com)y eating index score did experience lower risks of major chronic disease. However, these individuals also smoked less, exercised more, and had generally health(Buy now from http://www.drugswell.com)ier lifestyles; after adjusting for these variables, participants with the highest HEI scores did not experience signiﬁcantly better overall health(Buy now from http://www.drugswell.com) outcomes. This is consistent with a counterbalancing of beneﬁts and harm from following the USDA pyramid, and a lost opportunity to improve health(Buy now from http://www.drugswell.com).
10. THE 2005 USDA MYPYRAMID AND AN ALTERNATIVE
Because the scientific evidence had become so discordant with the 1992 Food Guide Pyramid, in 2005 the USDA released a new graphic and corresponding Website called MyPyramid ( http://www.mypyramid.gov/ ). An advantage of this new graphic is that the admonition to avoid dietary fat and eat large amounts of starch is no longer present. However, this new graphic consists of nothing more than colorful bands on a pyramid, and thus provides no dietary guidance at all. This represents a lost educational opportunity, but is consistent with the stated policy perspective of the USDA, which is that there is no such thing as a good for or a bad food, and that all foods can be part of a health(Buy now from http://www.drugswell.com)y diet.
Because of the serious deﬁciencies of the USDA pyramids, we have attempted to develop alternatives derived from the best available evidence. Thus our alternative health(Buy now from http://www.drugswell.com)y Eating Pyramid (Fig. 4 ) emphasizes weight control, giving attention to calories from all sources, and regular physical activity; health(Buy now from http://www.drugswell.com)y fats and health(Buy now from http://www.drugswell.com)y forms of carbohydrate; an abundance of fruits and vegetables; health(Buy now from http://www.drugswell.com)y sources of protein, which can be consistent with either a vegetarian or omnivore diet; and suggests sparing use of red meat, butter, reﬁned grain products, potatoes, and sugar. Trans fat does not appear because it has no place in an optimally health(Buy now from http://www.drugswell.com)y diet. A multiple vitamin is suggested for most people and moderate alcohol consumption is an option if not contraindicated. Data supporting the cardioprotective effects of moderate alcohol (in any form, wine, beer, or spirits) continues to accumulate. Policy makers are acutely aware of the risks entailed in promoting moderate alcohol consumption, so the pyramid is silent on this issue. Although clearly no alcohol is better than too much, a strong case can be made for including moderate consumption as part of a health(Buy now from http://www.drugswell.com)y diet for those without contraindications. One health(Buy now from http://www.drugswell.com) risk associated with moderate consumption is an increase in breast cancer, but it appears this may be conteracted with adequate folate intake.
To evaluate the overall impact of this alternative approach to food choices on risk of chronic disease, we have created a revised dietary score based on our health(Buy now from http://www.drugswell.com)y Eating pyramid (28). Better adherence to this alternative index of health(Buy now from http://www.drugswell.com)y food choice was associated with lower risk of risk of major chronic disease in both men and women, but the beneﬁts were due to reduced risk of cardiovascular disease, not cancer. Avoidance of overweight and regular physical activity, rather than speciﬁc food choices, is related to lower risk of many important cancers.
11. FUTURE NEEDS
Much research on the relation of diet to health(Buy now from http://www.drugswell.com) remains; almost all aspects are in need of additional refinement and many uncertainties exist. Important topics include the role of dairy products, the effects on health(Buy now from http://www.drugswell.com) of specific fruits and vegetables, the risks and benefits of vitamin supplements, and the effects of all aspects of diet during childhood and early adult life. The interaction of dietary factors with genetic predisposition is a topic of great interest, although its importance remains to be determined.
The amount of ongoing research on diet and health(Buy now from http://www.drugswell.com) is massive, and this should provide improved and more speciﬁc dietary guidance in the future. It will be important to evaluate the validity of this information in relation to long-term health(Buy now from http://www.drugswell.com) outcomes empirically. An additional challenge will be to convey this information to the public in a way that is strictly based on the best available scientiﬁc evidence. Agriculture is by far the largest and most powerful industry in the country, making it difﬁcult for the Department of Agriculture to develop objective nutritional guidelines because of its dual role as an industry advocate and provider of guidance to consumers. Dietary guidance should be developed in a setting that is insulated from political and economic interests.
A wealth of research from many lines of investigation indicates that dietary choices have an important impact on our long-term health(Buy now from http://www.drugswell.com). However, the Department of Agriculture has provided poor guidance to persons seeking to maintain or improve their long-term health(Buy now from http://www.drugswell.com). Alternative national guidelines that emphasize health(Buy now from http://www.drugswell.com)y forms of carbohydrate, fats, and protein are needed.
9 . National Research Council (U.S.) , Committee on Diet and health(Buy now from http://www.drugswell.com). Diet and health(Buy now from http://www.drugswell.com): implications for reducing chronic disease risk. Washington, DC: National Academy Press, 1989.
10. Kim EH, Willett WC, Colditz GA, et al . Dietary fat and risk of postmenopausal breast cancer in a 20-year follow-up . Am J Epidemiol 2006 ; 164 : 990 – 7 .
11 . Willett WC, Leibel RL. Dietary fat is not a major determinant of body fat. Am J Med 2002;113 Suppl 9B:47S–59.
Key Words: Cardiovascular disease , Nutrition , Mediterranean diet , DASH diet
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_12, © Humana Press, a part of Springer Science + Business Media, LLC 2009
Industrial and technological revolutions have resulted in dramatic shifts in the prevalence of several diseases over the last decades. Cardiovascular disease (CVD), in particular, has emerged as the dominant chronic disease in many parts of the world. Diet, tobacco smoking, physical inactivity, obesity, as well as hyperlipidemia, hypertension, and diabetes mellitus have contributed to the increasing morbidity and mortality from CVD. Thus, appropriate alterations of lifestyle and nutritional practices are of major importance in primary prevention of CVD. What a person routinely eats appears to play a central role in his or her long-term risk of CVD. Although much of the focus from the 1950s to the 1990s was on the contribution the diet made to blood levels of total cholesterol or low-density lipoprotein cholesterol (LDL-C), it has now been realized that this relationship is only one aspect of the diet’s role in contributing to CVD risk. Diet is thought to influence coronary heart disease through a number of mechanisms, including abnormal lipid levels, raised blood pressure, thrombotic tendency, endothelial dysfunction, systemic inflammation, insulin resistance, altered cardiac rhythm, and elevated oxidative stress (1).
Substantial research has examined the role of diet on CVD risk in terms of nutrients, food groups, or dietary patterns. On the one hand, nutrients including saturated fatty acids, trans fatty acids, and sodium have been proven to most signiﬁcantly heighten CVD risk, resulting in detrimental increases in blood cholesterol levels and blood pressure. On the other hand, there are numerous beneﬁcial nutrients including dietary ﬁ ber, various antioxidants (e.g., vitamins A, C and E), B vitamins (B 6 , B 12, and niacin), folic acid, omega-3 fatty acids, monounsaturated fatty acids, calcium, and potassium. Food groups such as fruits, vegetables, low fat dairy products, nuts, whole-grain cereals, fatty ﬁ sh, and olive oil have been linked to reduced CVD risk in many epidemiological studies (2). Finally, studies examining the effect of the overall diet on CVD risk have revealed that adherence to a “prudent” dietary pattern (characterized by higher intake of fruits, vegetables, legumes, whole grains, poultry, and ﬁsh), to a DASH-style diet, or to the
Major Dietary Recommendations for CVD Risk Prevention
Aim for balance between calorie intake and physical activity to achieve or maintain a health(Buy now from http://www.drugswell.com)y body weight. For overweight or obese subjects, a weight reduction program should be initiated
A wide variety of food items should be eaten
Consumption of a diet rich in vegetables and fruits, wholegrain cereals, and bread is recommended
Consumption of ﬁsh, especially oily ﬁsh, at least twice a week, lean meat and low fat dairy products should be emphasized
Limit saturated (animal) fat and partially hydrogenated fat intake by preferring the above-mentioned foods, as well as monounsaturated and polyunsaturated fats from vegetable and marine sources. Saturated fat should not exceed 10% of daily caloric intake
Reduction in beverage intake and in foods with added sugars is desirable
Foods should be prepared with little or no salt. Emphasis needs to be placed on fresh or frozen unsalted foods. Many processed and prepared foods, including bread are rich in salt
In case of habitual alcohol consumption, this should be done in moderation
traditional Mediterranean diet is associated with a lower risk of coronary heart disease and stroke and with greater life expectancy, independent of other lifestyle factors (3–5). It should be noted, however, that evidence deriving from observational epidemiology studies has not always been conﬁrmed by interventional trials.
According to the guidelines of the American Heart Association and the European Society of Cardiology, dietary changes constitute an integral part of cardiovascular risk management (2,6). All individuals at high risk for CVD should be given professional and individualized advice on the food options that best reduce cardiovascular risk. A varied and energy-balanced regimen, together with regular exercise, is of critical importance for the preservation of cardiovascular health(Buy now from http://www.drugswell.com) (Table 1 ). Moreover, intentional weight loss in obese patients can improve or prevent many of the obesity-related risk factors for CVD. It is now clear that body fat, and in particular intraabdominal visceral fat, is a metabolically active endocrine organ that is capable of synthesizing and releasing into the bloodstream an important array of peptide and non-peptide compounds that may play a role in cardiovascular homeostasis.
The assessment and subsequent treatment of CVD begins with the identification of risk factors, particularly those that are nutrition-related. Careful and detailed assessment of nutritional status should focus on potential risk factors including diabetes, overweight/obesity, hypertension, and prothrombotic or proinflammatory states including elevated homocysteine levels, and should consider food choices, physical activity levels, and patients’ readiness to change their habits toward a health(Buy now from http://www.drugswell.com)ier pattern. Overweight is classified as a body mass index (BMI) of 25.0–29.9 kg/m2. Class 1 obesity refers to a BMI of 30.0–34.9, class 2 obesity to a BMI of 35.0–39.9, and class 3, or extreme obesity, to a BMI of >40 kg/ m2(7). A BMI of >30 kg/m 2 or >27 kg/m2, along with comorbidities, calls for immediate initiation of weight management including pharmacological therapy. Weight management with life style modifications should also be considered for those subjects with BMI ³ 25 kg/m2. Moreover, the association between both increased waist circumference (WC) or waist to hip ratio (WHR) and greater risk of CVD development has been demonstrated in both cohort and case-control studies. Evidence from these sources shows WC to be a better marker of intraabdominal fat content than WHR. In the context of cardiovascular health(Buy now from http://www.drugswell.com), WC is shown to be an extremely useful marker of risk. Unlike BMI alone, WC is able to reflect visceral fat accumulation, which is associated with increased CVD risk and related metabolic risks to a greater extent than simply subcutaneous body fat alone. Larger WCs (>40 in. for men and > 35 in. for women) are closely linked to insulin resistance, sleep apnea, and inflammation, which are parti-cularly dangerous for the patient with coronary heart disease (CHD) (7). Nutritional risk factors such as high intake of saturated fatty acids (SFA), trans fatty acids (TFA), cholesterol, and sodium as well as low intake of protective foods such as soluble fiber, fatty acids (including omega-3, or n-3) and a variety of fruits and vegetables should be thoroughly assessed through detailed diet histories (1).
There is a wide variety of lifestyle and pharmacological treatments available for the prevention and treatment of CHD. The combination of nutrition management and behavioral modification with appropriate pharmacotherapy has been shown to be the
Dietary Recommendations for Achieving Desirable Blood Lipid Proﬁle and Especially LDL-C Levels (8)
Limit food items high in saturated fats
Replace saturated fats with lower-fat foods
Increase consumption of food items with unsaturated fat
Carefully monitor intake of food items high in cholesterol
Severely limit food items containing trans fatty acids
Increase food items rich in viscous ﬁ ber
Increase food items containing stanol/sterol esters (special margarines, fortiﬁ ed orange juice, special cocoa/chocolate bars)
In case of hypetriglyceridemia:
Limit dietary fat intake between 25 and 35% of total daily calories, as well as simple sugars and rapidly hydrolyzed starches, which have a greater glycemic effect than more complex carbohydrates
Limit excessive alcohol intake, which has a detrimental effect on triglycerides levels
There is accumulating evidence to support the beneficial influence of omega-3 fatty acids in the management of hypertriglyceridemia either through diet or supplements, but very high doses may be needed (see relevant chapter on pharmacotherapy)
Therapeutic Lifestyle Changes for Patients with Already Established CVD (9)
Nutrient Recommended Intake as percent of total calories
|Total fat a||25–35%|
|Saturated fat||Less than 7%|
|Polyunsaturated fat||Up to 10%|
|Monounsaturated fat||Up to 20%|
|Carbohydratesb||50–60% of total calories|
|Cholesterol||Less than 200 mg/day|
|Plant stanols/sterols||2 g/day|
|Increased soluble ﬁ ber||10–25 g/day|
|Total calories||Balance energy intake and expenditure to|
|maintain desirable body weight and to|
|prevent weight gain|
|Physical activity||Include enough moderate exercise to expend|
|at least 200 kcal/day|
a The 25–35% fat recommendation allows for increased intake of unsaturated fat in place of carbohydrates in people with the metabolic syndrome or diabetes. b Carbohydrates should come mainly from foods rich in complex carbohydrates. These include grains (especially whole grains), fruits, and vegetables. c Soy protein may be used as a replacement for some animal products.
most effective method of treatment. For patients with already-established CHD or dyslipidemia, it is recommended that dietary and lifestyle changes are made first, and pharmacologic treatment is added as needed (8,9). Tables 2 and 3 summarize the dietary recommendations for patients with hyperlipidemia and already-established CHD, respectively. Pharmacotherapy is beyond the scope of this Chapter.
Dietary intervention by a registered dietitian, usually over the course of two to six sessions, has been shown to be most effective at helping patients achieve these goals. Nutrition therapy provided by a registered dietitian over a period of 6 weeks to 6 months can result in substantial changes in dietary habits. The ﬁrst visit length is usually 45–90 min and subsequent visits should last between 30 and 60 min.
Reducing the total amount of fat in the diet has long been a method for decreasing the risk of CHD. Early studies also suggested that the type of fat might be more important than the total amount of fat in the diet. Two secondary prevention trials testing total fat reduction failed to find a significant reduction in serum cholesterol or CHD events (10,11). Data from the largest analysis done in this area indicate that types of fats may play a more important role in CHD risk than total fat intake. The Nurses’ health(Buy now from http://www.drugswell.com) Study revealed that higher intakes of TFA and, to a smaller extent SFA, are associated with increased risk. In contrast, higher intakes of nonhydrogenated polyunsaturated (PUFA) and monounsaturated fatty acids (MUFA) correlate with decreased risk (12).
As shown in Table 3 , total fat intake can cover up to 35% of total daily calories, as long as it comes mainly from MUFA. SFA should be limited to <7% of energy, TFA to <1% of energy, and dietary cholesterol to <200 mg/day. Evidence for the beneﬁ ts of lowering dietary SFA was provided by the Seven Countries Study (13) in which regional differences in death from CHD were strongly correlated with SFA intake. Many population studies have since then provided evidence of associations between diets high in SFA and increased total cholesterol and LDL-C levels, as well as increased risk of both CHD and CVD (14). When SFA were replaced by unsaturated fats, total plasma cholesterol was lowered (15). Moreover, substituting PUFA for SFA does appear to be beneﬁ cial in lowering serum cholesterol and reducing cardiovascular mortality, as demonstrated by the Finnish Mental hospital Study, the Los Angeles Veteran Study, the Oslo Diet-Heart Study, and the MRC study (1).
A recent study, known as The Omniheart Randomized Trial, evaluated the effects of three reduced SFA and dietary cholesterol diets that varied only in macronutrient content (16). All three of the diets provided 6% of energy from SFA. Both the carbohydrate-rich and protein-rich diets provided 27% energy from total fat, although the content of the carbohydrate and protein varied. The carbohydrate-rich diet consisted of 58% from carbohydrate, whereas the protein-rich diet provided 25% of energy from protein. The third diet, the unsaturated fatty acid-rich diet, was higher in fat, providing 37% of energy from total fat (21% of which was MUFA). Both the protein and the unsaturated fatty acids-rich diet improved triglyceride levels statistically. The unsaturated fatty acids diet also improved high-density lipoprotein cholesterol (HDL-C) levels. These results suggest that partial substitution of carbohydrate for protein or unsaturated fatty acids can favorably affect both blood triglycerides and HDL-C. Data from the Nurses health(Buy now from http://www.drugswell.com) Study also suggest that the highest (5.7 g/day) vs. the lowest (2.4 g/day) quintile of TFA intake is associated with an increase in CHD risk (17). Other studies continue to emerge that further bolster the argument to avoid trans fatty acids (14).
The most commonly occurring MUFA in the diet is oleic acid (C18:1), which is abundant in olive and canola oils as well as in nuts. There has been continued debate over the past several years on whether MUFA or PUFA should replace SFA in the diet. The early metabolic studies by Mattson and Grundy (18) revealed that MUFA lowered LDL-C concentrations with no effect on HDL-C levels, whereas PUFA lowered both LDL-C and HDL-C levels. Subsequent studies, even including metaanalyses, have suggested that the effects of MUFA and PUFA on plasma lipoprotein proﬁles are similar (15). Moreover, dietary fat may inﬂuence the risk of CHD by altering the susceptibility of lipoproteins to oxidation. Previous work has shown that, in the test tube, LDL-C particles enriched in MUFA are less susceptible to oxidation than particles enriched in n-6 PUFA (19). These results have also been supported by a study that examined the oxidation of LDL-C from subjects consuming diets enriched in olive oil (MUFA), rapeseed oil (MUFA plus n-3 PUFA), or sunﬂ ower oil (n-6 PUFA) (20). LDL-C oxidation was lowest in the olive oil group, intermediate in the rapeseed oil group, and highest in the sunﬂower oil group. This indicated that MUFA reduced LDL-C oxidation compared with n-6 PUFA. Also, when comparing MUFA and PUFA, it may be important to distinguish between n-6 and n-3 PUFA. The potential health(Buy now from http://www.drugswell.com) beneﬁts of n-3 PUFA are being presented in the supplements section.
Finally, epidemiological evidence and intervention studies clearly show that in humans SFA signiﬁcantly worsen insulin-resistance, while MUFA and PUFA improve it through modiﬁcations of the composition of cell membranes. Shifting from SFA to MUFA intake can also affect blood pressure signiﬁcantly, especially by reducing diastolic blood pressure (21).
Therefore, on the basis of current evidence, emanating mainly from observational studies, patients should be encouraged to focus on replacing the main sources of SFA and TFA. SFA are generally found in animal fats in foods such as meat and dairy. TFA are generally produced by hydrogenation of vegetable oils and found in food items such as bakery goods or fried foods. These foods should be replaced with foods high in MUFA and PUFA, such as olive oil, nuts, seeds, and ﬁ sh.
Protein does not directly affect serum LDL-C levels or other lipid profile components. By encouraging patients to replace some of their animal protein sources with plant-based protein sources however, dietitians can indirectly address intake of total dietary fat, particularly in the form of saturated fat. Plant sources of protein include vegetables, legumes, whole-grains, and nuts. In addition, patients should be educated on correct portion sizes of protein rich foods.
Epidemiological evidence from human subjects suggests that high soybean consumption, the main dietary source of isoflavones, may be cardioprotective. Existing data suggest that soybean food and soybean protein interventions may have a beneficial effect on certain aspects of the lipoprotein profile, while there is limited data to support a lipid-lowering effect of isoflavone extracts. Available evidence in this area remains minimal however, and, at this time, the only potential link that has been suggested is between soy consumption and lowered LDL-C. No data have shown substantial benefits of soy protein consumption on HDL-C, total cholesterol, triglycerides, or lipoprotein(a). Data from in vitro and animal experiments are currently emerging and suggest that isoflavones may be cardioprotective by mechanisms independent of blood lipids, but these underlying mechanisms remain only partly understood. As a result, more recent research efforts have focused on the potential effects of phyto-oestrogens on blood pressure, in vivo measures of vascular function, such as flow-mediated dilation and novel biomarkers of CHD risk (i.e., inflammatory factors, coagulation, and fibrinolytic factors as well as markers of LDL-C oxidation). To date these studies have not been systematically reviewed. Data from human studies on the effects of soybean foods and soybean protein on blood pressure are equivocal, but it is clear that there is no evidence for an effect of isoflavone extracts on blood pressure. Moreover, although there is growing interest in the potential direct effects of isoflavones on the arterial wall, the available data from human studies are inconclusive (22).
Consumers should be advised that, although FDA issued a health(Buy now from http://www.drugswell.com) claim in 1999 stating that 25 g/day soy protein was associated with reduced risk of CHD, the current body of research in this area does not appear to fully support this claim. Soy products such as tofu, soy butter, soy nuts, or some soy burgers may be beneﬁcial to cardiovascular and overall health(Buy now from http://www.drugswell.com) because of their high content of PUFA, ﬁber, vitamins, and minerals and low content of SFA. Therefore, using these and other soy foods to replace foods high in animal protein that contain saturated fat and cholesterol may confer beneﬁ ts to cardiovascular health(Buy now from http://www.drugswell.com) (23).
The relationship of carbohydrate dietary intake with CHD appears to be mediated by several, mainly indirect, mechanisms: contribution to total energy intake and effect on overweight and obesity, influence on central obesity, effects on plasma lipids (especially triglycerides), and effects on glycemic control. The balance between carbohydrates and fat as sources of energy as well as the fiber component of the diet are also areas of interest. In feeding experiments, an increase in dietary energy from carbohydrates is usually associated with a moderate increase in fasting plasma triglyceride levels in the first few weeks, but these return to near baseline levels in the following weeks (24).
The effect of a high-carbohydrate diet on HDL-C and thereby on the total to HDL cholesterol ratio, as well as on the particle size of LDL-C, are matters of scientiﬁ c interest as is the inﬂuence on vascular function and subsequent risk of CHD. Diets high in carbohydrates appear to reduce HDL-C levels and increase the fraction of small dense LDL-C, both of which may adversely impact vascular disease. This dyslipidemic pattern is consistent with the elevation of plasma triglycerides. Currently, there is no clear evidence that the risk of CHD is independently altered by carbohydrate levels in the diet (25) . On the contrary, postprandial hyperglycemia is increasingly recognized as an independent risk factor for cardiovascular disease. Glycemic “spikes” may adversely affect vascular structure and function via multiple mechanisms, including (acutely and/or chronically) oxidative stress, inﬂ ammation, low-density lipoprotein oxidation, protein glycation, and procoagulant activity. The glycemic index of foods might also be a determinant of the extent to which carbohydrates can inﬂuence the glycemic status. Low glycemic index diets in hyperlipidemic and type 2 diabetic subjects have been associated with signiﬁ cant reductions in LDL-C and triglycerides with no effect on HDL-C levels (26,27).
In attempting to follow a low-fat diet, many patients erroneously substitute carbohydrates for SFA. Although this does generally reduce overall caloric intake, it does not effectively reduce cardiovascular risk. In fact, it can even exacerbate related metabolic risk factors, including insulin resistance, unless careful choices of low glycemic index foods are made.
A diet that provides 25–30 g (or 10–13 g/1,000 Kcal) of total dietary fiber, including at least 7–13 g of soluble fiber, is a well tolerated and effective way to decrease lipid levels and CHD risk (14). Foods rich in soluble fiber include oatmeal, oat bran, barley, fruits with skins intact, eggplant, Brussels sprouts, and ground flaxseed. Moreover, beans and legumes (such as black-eyed, soy, and kidney beans) are particularly good sources of fiber. Soluble fiber binds to LDL-C and carries it out of the body, improving the patient’s overall lipid profile.
High ﬁber diets are also associated with other health(Buy now from http://www.drugswell.com) beneﬁts including improved glycemic control and reduced body weight due to increased satiety. Patients must be educated in reading food labels in order to better identify truly whole grains. The ﬁrst ingredient reported on the labels must be a whole grain such as wheat, oats, or barley. Likewise, breads must list the ﬁrst ingredient as “whole grain ﬂ our.”
Several studies indicate that moderate drinking is associated with a decreased risk of CHD (28) but the exact mechanisms underlying risk reduction due to moderate alcohol consumption remain largely unknown. The beneficial effects of alcohol could be due to an increase in HDL-C cholesterol and apo A-1 and/or a modest improvement in hemostatic factors (29). Alcohol may also be associated with lower LDL-C levels, but it is unclear whether this is independent of other dietary factors. A subset of heavier drinkers demonstrates a substantial increase in triglyceride levels, but this is infrequently seen with light/moderate drinking. Moreover, antithrombotic actions of alcohol could partially account for the lower CHD risk at very light drinking levels (e.g., several drinks per week) observed in several epidemiologic studies. During the last few years, both epidemiological and experimental studies have supported the hypothesis that, in addition to ethanol, certain substances in wine (especially red wine) have cardioprotective effects. The best studied of these substances are polyphenols, categorized as flavonoids [mainly flavonols (quercetin and myricetin), flavanols or flavan-3-ols (catechin and epicatechin), and the anthocyannins] and nonflavonoids [including the stilbenes (resveratrol), hydroxynnamates (caffeic, caftaric, and coutaric acids), and the hydroxybenzoates] (30) . Data suggest that ingestion of grape flavonoids is followed by a reduction in platelet activation (31), inflammation and low-density lipoprotein oxidation (32), improvement of endothelial function due to induction of nitric oxide release with the subsequent effect of vasorelaxation (33) and elevation in HDL-C levels (34), but these data need to be confirmed and expanded.
It has been observed that the lipimic proﬁle differs, among drinkers of different spirits, with wine drinkers having the most favorable CHD risk proﬁle. Differences in drinking patterns among subjects consuming different beverage types could also play a role in terms of their effects on CHD risk factors. The question of whether the different risks and beneﬁts associated with the different types of alcoholic beverages – beer, wine, and spirits – is still unresolved, but it seems likely that ethyl alcohol is one of the major factors lowering CHD risk (35).
It has been shown in both the US National Alcohol Survey and a Finnish study that light to moderate drinkers who experienced occasional bouts of heavy drinking had a signiﬁcantly higher mortality rate compared with those who had the same average intake (36,37). A recent large study from Denmark also showed that, for the same average intake, binge drinkers had a higher all-cause mortality than steady drinkers (38). Moreover, in a study of 11,511 cases of acute myocardial infarction or fatal CHD and 6,077 controls in New South Wales, Australia, it was shown that individuals who had a steady small intake of alcohol had lower odds for fatal CHD while those who had the same average intake, but consumed their alcohol once or twice per week, did not (39). In the health(Buy now from http://www.drugswell.com) Professionals study, Mukamal et al. recently showed that cardioprotection seemed to be more strongly related to the frequency of intake rather than to the amount of alcohol ingested (40). This study has very recently been followed by a more detailed description of the mediators of the effect of drinking pattern, namely HDL-C, hemoglobin A1c and ﬁbrinogen, as responsible for 75–100% of the association observed (41). In conclusion, these ﬁndings strongly suggest that drinking pattern – steady vs. binge drinking – plays a role in the apparent cardioprotective effect of alcohol. Finally, recent reports suggest that drinking during a meal, in a true Mediterranean diet pattern, is beneﬁcial for both CHD and hypertension, while alcohol taken in between meals does not show any substantial beneﬁ t (42,43).
Moderate drinking is deﬁned as no more than one drink per day for women and no more than two drinks per day for men, ideally consumed with meals. A 12-ounce bottle of beer, a 4-ounce glass of wine, and a 1½ shot of 80-proof spirits all contain the same amount of alcohol (one half ounce) (2). People who do not habitually consume alcohol are not advised to incorporate alcoholic drinks into their diets in order to reduce their CHD risk, and individuals who consume alcohol are advised to do so in moderation, as heavy consumption is associated with an increase in the prevalence of the metabolic syndrome, type 2 diabetes mellitus, stroke, peripheral arterial disease, and overall CHD (44). It is also important for patients to remember to limit their intake of alcohol within a reasonable range to prevent weight gain, as alcohol supplies calories with limited nutritional beneﬁ ts.
Although there has been a consensus that fruits and vegetables should be considered as cornerstones in a heart health(Buy now from http://www.drugswell.com)y diet, it is only recently that solid epidemiological evidence has linked these two food groups together. The largest relevant study has reported a significant inverse association between consumption of fruits and vegetables, particularly green leafy vegetables and vitamin C-rich fruits and vegetables, and risk of CHD (45). Every single serving per day of fruits and vegetables was associated with a 4% decrease in CHD risk. It is still unclear whether the fruits and vegetables themselves have cardioprotective features, or whether they simply displace from the diet other foods with harmful properties. Two examples of diet patterns that are consistent with the AHA guideline to increase fruits and vegetables are the DASH Diet and the TLC (Therapeutic Lifestyle Changes) Diet. Both recommend consumption of at least 8–10 servings of fruits and vegetables combined per day (2). However, the biologic mechanisms whereby fruits and vegetables may exert their beneficial effects are not entirely clear and are likely to be numerous. Several nutrients and phytochemicals, including fiber, potassium, folate, lycopene, and polyphenols, could be independently or jointly responsible for the apparent reduction in CHD risk. Functional aspects of fruits and vegetables, such as their low dietary glycemic load and low energy density, may also play a significant role. Moreover, fruit and vegetable consumption has been positively associated with total adiponectin levels, an adipocytokine that has been shown to improve insulin action as well as glucose and lipid metabolism (46). Additionally, consumption of fruits has been positively associated with high molecular weight adiponectin, the fraction of adiponectin that has been proposed to be more closely associated with insulin resistance and the presence of metabolic syndrome (47). Although it is important to continue our quest for mechanistic insights, given the great potential shown in epidemiology studies, increased fruit and vegetable intake is recommended (48). A variety of deep colored fruits and vegetables is recommended because of their high micronutrient content. Moreover, due to their significant nutrient density and fiber content, fruits and vegetables at the commencement and in between meals may play a role in inducing satiety, which would in turn reduce calorie intake and promote weight loss.
Several epidemiological studies have reported that whole-grain intake is protective against CVD, diabetes, and obesity. Whole grains are concentrated sources of dietary fiber, resistant starch, and oligosaccharides, i.e. carbohydrates that escape digestion in the small intestine and are fermented in the gut, producing short chain fatty acids. Short-chain fatty acids lower colonic pH, serve as an energy source for the colonocytes, and may alter blood lipids. Moreover, whole grains are rich in antioxidants, including trace minerals and phenolic compounds, which have been linked to disease prevention. Finally, whole grains mediate insulin and glucose responses and also contain many other compounds, such as phytates, phyto-oestrogens (e.g., lignans), plant sterols/stanols, vitamins, and minerals that may protect against chronic diseases (49). Recently, intake of whole grains has been associated with higher adiponectin levels. In a cross-sectional study of 220 apparently health(Buy now from http://www.drugswell.com)y adult Mediterranean women, it has been shown that adherence to a dietary pattern characterized by high intake of whole-grain cereals and low-fat dairy products, as well as low intake of refined cereals, was significantly and positively associated with adiponectin levels after controlling for potential confounders (50). Moreover, intake of whole grains was associated with a reduced incidence of fatal and nonfatal CHD in many large prospective population studies (51) . These studies suggest a 20–30% reduced risk of CHD in persons with a daily intake of ³3 servings of whole-grain food items.
Several RCTs examining the effect of whole grain consumption on CHD risk factors, such as blood lipids, hypertension, and insulin resistance, as well as on body weight and inﬂammatory markers, are currently in progress. Current guidelines for whole grain intake emanate mainly from epidemiological studies that cannot prove causality. The recommended amount of grain servings per day is 6–8 and the AHA recommends that at least half of these should come from whole grain sources (2). Servings size examples include one slice of wholemeal bread, 1 oz dry wholegrain cereal, and half cup cooked brown rice, wholegrain pasta or cereal.
Nuts, which are naturally high in MUFA and PUFA, have been associated with LDL-C lowering effects and an overall improvement in lipid profiles (52). The species studied so far include walnuts, almonds, legume peanuts, macadamia nuts, pecans, and pistachio nuts. Collectively, clinical studies indicate that inclusion of nuts in a lipid-lowering diet has favorable effects, especially on LDL-C levels; however, existing studies do not provide unequivocal evidence of an additive effect of nuts to the effects of a low SFA diet per se. The fatty acid profile of nuts (high in unsaturated fatty acids and low in saturated fatty acids) lowers blood cholesterol by altering the fatty acid composition of the diet as a whole. Nuts are also a rich source of dietary fiber and micronutrients, such as phytosterols, arginine, potassium, copper, magnesium, selenium, and vitamin E (25). Frequent nut and seed consumption has been associated with lower levels of inflammatory markers (namely C-reactive protein and interleukin-6), lower levels of fibrinogen, and lower blood pressure (provided that they are unsalted) (53,54).
It must, however, be recognized that the high-fat content of nuts makes them high in calories too. Advice to include nuts in the diet must be tempered in accordance with the desired energy balance. Although further research is needed to characterize the independent protective effects of these food items against CHD and to identify the mechanisms of such protection, available evidence suggests that nuts should be recommended as part of an energy appropriate health(Buy now from http://www.drugswell.com)y diet, which is intended to reduce the risk of CHD. Federal guidelines recommend nut consumption in ¼ cup daily or up to 5 oz per week (55). Patients should be encouraged to focus on isocalorically substituting nuts for other foods in their diet to prevent excess calorie intake and subsequent weight gain.
Dairy products, especially milk, have been considered as potential promoters of CHD because they are sources of cholesterol and SFA but the short-chain fatty acids and the long-chain stearic acid, which do not adversely affect cholesterol levels, are considerable parts of the SFA in milk fat. Milk intake is probably positively related to blood lipid levels, but the effect shown in many studies is either trivial or absent. In fact, milk supplementation led to a decrease in blood lipids in some studies, and it has also been suggested that milk and milk products may contain antiatherogenic bioactive substances to negate the effects of SFA and cholesterol (56). There is also growing evidence supporting a protective role of dairy consumption (especially low-fat); for example an inverse relationship has been observed between consumption of dairy products and the odds of having acute coronary syndrome (57). A dietary pattern that highlights the possible protective role of low-fat dairy products is the DASH diet. The DASH dietary pattern emphasizes fruits, vegetables, and low-fat dairy products and is reduced in saturated and total fats and cholesterol. This diet has been shown to lower blood pressure in men and women, those with or without hypertension, those who are young or old, and in African Americans and non-African Americans (58).
Calcium, bioactive peptides, and several as of yet unidentiﬁed components in whole milk may protect from hypertension. Folic acid, vitamins B6 and B12 as well as other components may contribute to low homocysteine levels, while conjugated linoleic acid may have hypolipidemic and antioxidative (and thus antiatherogenic) effects (59) . Additionally, hypocholesterolemic or hypotensive properties have been attributed to fermented dairy products (e.g., yogurt), although the existing data do not allow for deﬁ nitive conclusions. It has also been proposed that different bacterial strains in fermented milk products have different cholesterol-reducing properties. Still, apparently a necessary condition is that the bacteria, called probiotic bacteria, are able to survive the gut and colonize the intestine (60). These data need to be conﬁrmed by future studies.
Although much of the research to date has focused on individual nutrients and their effect on CHD, broader research is now investigating the impact of diet as a whole. People consume meals consisting of several food items containing a broad combination of nutrients. Therefore, complicated or cumulative intercorrelations and interactions between nutrients and food groups should be studied. Rather than assessing single nutrients, foods, or food groups, it has been suggested that a holistic dietary approach, which examines the effect of dietary patterns in terms of chronic disease prevention and treatment, may be a more valuable approach to evaluate associations between diet and biological markers and/or disease outcomes (3).
The methodology for defining dietary patterns consists of three main approaches: analysis of dietary indices, cluster analysis, and factor analysis. The last two approaches often reveal a “prudent” dietary pattern, mainly characterized by higher intakes of fruits, vegetables, legumes, fish, poultry, and whole grains, and a “Western” dietary pattern, characterized by higher intakes of red and processed meats, sweets/desserts, French fries, and refined grains. Adherence to the “prudent” dietary pattern has been associated with significantly lower relative risks for CHD after adjustment for several factors known to affect CHD risk in men. Those at the highest quintile of adherence showed a 30% lower risk (61). The respective effect in women was 24% lower relative risk for CHD (62). Moreover, in the health(Buy now from http://www.drugswell.com) Professionals Follow-up Study, significant positive correlations between a “Western” dietary pattern and blood insulin, C-peptide, leptin, and homocysteine concentrations were observed. An inverse correlation with plasma folate concentrations was also noted. The “prudent” dietary pattern was positively correlated with plasma folate and inversely correlated with insulin and homocysteine concentrations (63). Adherence to the “prudent” pattern has also been inversely associated with plasma concentrations of CRP and E-selectin, after adjustment for age, body mass index, physical activity, smoking status, and alcohol consumption (64), as well as with lower risk for type II diabetes both in women (65) and men (66), with enhanced insulin sensitivity (67) and with stroke prevention (68).
The term “Mediterranean diet” has been widely used to describe the traditional dietary habits of people in Crete, South Italy, and other Mediterranean countries during the 1960s. It is schematically depicted as a food pyramid. This dietary pattern is characterized by plentiful plant foods (fruits, vegetables, breads, other forms of cereals, beans, nuts, and seeds), olive oil as the principal source of fat, moderate amounts of dairy products (mainly cheese and yogurt), low to moderate amounts of fish and poultry, red meat in low amounts and wine consumed in low to moderate quantities, usually with meals (69). There are several beneficial nutrients that are abundant in the Mediterranean diet, such as MUFA, a balanced ratio of omega-6/omega-3 essential fatty acids, high amounts of fiber, antioxidants such as vitamins E and C, resveratrol, polyphenols, selenium, glutathione, and many others that are currently under investigation.
In a recent systematic review, Serra-Majem et al. reviewed and analyzed the experimental studies on Mediterranean diet and disease prevention (70). Most of the clinical trials exploring the effect of Mediterranean diet on lipids levels found reductions in total and low-density lipoprotein cholesterol (LDL-C), triglycerides, apolipoprotein B, and very-low-density lipoprotein cholesterol, and an increase in HDL cholesterol. A decrease in the number of small LDL-C particles has also been observed in some studies. Endothelial function improved with the adoption of the Mediterranean diet, and endothelial dependent vasodilatation was increased by adding nuts to the Mediterranean diet. Insulin resistance and metabolic syndrome were reduced after shifting to a Mediterranean diet, but some studies showed no effects on insulin or glucose levels. Importantly, studies addressing secondary prevention of cardiovascular disease have shown a signiﬁ cantly reduced odds ratio for fatal myocardial infarction (between 0.25 and 0.7).
More speciﬁcally the results of three studies examining the effects of Mediterranean diet in the secondary prevention of CHD are of great interest. The Indo-Mediterranean diet Heart Study explored the cardioprotective effects of a Mediterranean style diet rich in a-linolenic acid vs. a Step I National Cholesterol Education Program (NCEP) prudent diet in 1,000 patients with angina pectoris, myocardial infarction, or surrogate risk factors for CHD (71). Total cardiac end points were signiﬁcantly fewer in the Mediterranean diet group compared with controls. Sudden cardiac deaths and nonfatal myocardial infarctions were also reduced. The investigators noted that in the Mediterranean diet group, patients with preexisting CHD had signiﬁcantly greater beneﬁts compared with such patients in the control group and concluded that an Indo-Mediterranean diet, rich in a -linolenic acid, might be more effective in primary and secondary prevention of CHD than the conventional step I NCEP prudent diet. Moreover, the Lyon Diet Heart Study, a randomized secondary prevention trial aimed at testing whether a Mediterranean-type diet may reduce the rate of recurrence after an initial myocardial infarction (72), focused on cardiac death and nonfatal myocardial infarction, unstable angina, stroke, heart failure, and pulmonary or peripheral embolism. In the Mediterranean diet group, all the above-mentioned outcomes were signiﬁcantly reduced compared with a prudent Western-type diet group during the 4 years of follow-up after the ﬁrst infarction. Finally, the GISSI-Prevenzione clinical trial explored whether simple dietary advice to increase the consumption of Mediterranean foods, given in a clinical setting, leads to reduced mortality after a myocardial infarction (73). When the range of observed scores of adherence to the Mediterranean-like dietary pattern was split into equal quartiles, the chance of death was decreased by 31%, 34%, and 49% for the second, third, and fourth quartiles, each compared with the ﬁ rst (depicting the least adherence), after adjustment for nondietary confounding variables. Overall, a 10% (one unit) increase in the dietary score reduced the risk of mortality by 15%. It has been concluded that patients with myocardial infarction can respond positively to simple dietary advice, and this can be expected to lead to a substantial reduction in the risk of early death. Regardless of any drug treatment prescribed, clinicians should routinely advise patients with myocardial infarction to increase the frequency of consumption of foods belonging to what is perceived as “Mediterranean diet.”
Dietary strategies to lower blood pressure play an important role in reducing overall CHD risk. The most well known controlled feeding study to test the dietary affects on hypertension is known as DASH (74). The results of the study clearly show that a diet high in fruits, vegetables, and low-fat dairy products, but low in saturated and total fat, reduces blood pressure in hypertensive and normotensive individuals (more so than the control diet). The composition of the DASH diet is 27% calories from total fat, 6% calories from SFA, 18% calories from protein, 55% calories from carbohydrate, 150 mg cholesterol and two levels of sodium intake − 2,400 or 1,500 mg. The calcium, magnesium and fiber content of the diet also stand out as high when compared with the typical American diet, with 1,250 mg calcium, 4,700 mg potassium, and 30 g fiber. The DASH diet was demonstrated to be effective as first-line therapy in individuals with stage I isolated systolic hypertension (i.e., with a systolic blood pressure of 140–159 mmHg and a diastolic blood pressure below 90 mmHg), with 78% of the persons on the DASH diet reducing their systolic blood pressure to <140 mmHg, in comparison to 24% in the control group (75). DASH has also be proven to be effective in lowering plasma levels of total and LDL-C but these changes were also accompanied by a reduction in HDL-C levels. While the Framingham risk score improved as a result of the impact on total and LDL-C as well as on blood pressure, the impact of the associated reduction in HDL-C needs to be assessed (76).
Furthermore, the PREMIER trial evaluated the effects of simultaneously implementing the DASH diet and established lifestyle recommendations for hypertension (weight loss, sodium reduction, increased physical activity, and limited alcohol intake) in free-living individuals. Participants in both intervention groups (established guidelines plus DASH vs. established guidelines) lost weight and reduced dietary sodium and fat intakes during the 18 months. In the established plus DASH group, participants made additional dietary changes, signiﬁcantly increasing their intakes of fruits, vegetables, and dairy products and further reducing their intake of saturated and total fats. As a consequence, their hypertension status improved (77).
Fish oil, rich in omega-3 PUFA, is thought to contribute to the prevention or alleviation of many illnesses, though the most established benefits associated with fish oil are cardioprotective. Beneficial effects associated with fish oil include ameliorating arrhythmia, lowering serum triglycerides, decreasing thrombosis and inflammation, and improving endothelial function (78–80). The active ingredients are thought to be the long chain docosahexaenoic acids (DHA) and eicosapentaenoic acids (EPA). DHA and EPA rich oils are found in fatty fish such as salmon, mackerel, lake trout, herring, sardines, and albacore tuna. Currently, the AHA recommends consuming fatty fish at least twice a week (~8 oz per week). Eating more servings of fish per week is beneficial, but some fish, particularly tuna, may contain high amounts of contaminants such as methyl mercury. Sensitive subgroups of the population, primarily children and pregnant women, are advised by the FDA to avoid eating those fish with the potential for the highest level of mercury contamination (e.g., shark, swordfish, king mackerel, or tilefish), eat up to 12 oz (two average meals) per week of a variety of fish and shellfish that are lower in mercury (e.g., canned light tuna, salmon, pollock, catfish), and check local advisories about the safety of fish caught by family and friends in local lakes, rivers, and coastal areas (81). For those who are already diagnosed with heart disease, the AHA recommends taking 1,000 mg a day of DHA plus EPA from fish oil, preferably from fatty fish, but supplements can augment the amount taken in the diet and should be taken under the supervision of a doctor. Supplementation of 2,000–4,000 mg of DHA and EPA may also be beneficial for those who have hypertriglyceridemia (82). The FDA does not recommend taking more than 3,000 mg without consulting a physician due to risks that include bleeding associated with these supplements (see also chapter on hyperlipidemia).
a-Linolenic acid (ALA) is another form of omega-3 fatty acid derived from plant sources such as soybeans, ﬂ axseed, and walnuts. ALA is a precursor molecule to EPA and DHA, and requires several metabolic steps before it can exert comparable beneﬁ ts. Only 5–15% of ALA is converted into more active compounds, however, making it overall a less attractive source of long chain polyunsaturated fats. Trials, like the Lyon Diet Heart Study, which showed that ALA consumption in the context of a Mediterranean diet reduced total and cardiovascular mortality as well as nonfatal myocardial infraction, support the use of ALA and ﬁsh oil in the secondary prevention of CHD (1). However, at present, the body of research concerning the cardioprotective beneﬁ ts of ALA is not conclusive.
Plant sterols (b-sitosterol, campesterol, and stigmasterol) and their saturated derivatives, the stanols (sitostanol and campestanol), are the naturally occurring equivalents of the mammalian sterol cholesterol. Edible oils, seeds, and nuts have a high content of plant sterols. The Western diet contains about 100–300 mg/day of plant sterols and 20–50 mg/day of plant stanols (83). Because of their structural similarity to cholesterol, plant sterols and stanols can replace cholesterol in the human body; they decrease total cholesterol and LDL-C levels by reducing dietary and biliary cholesterol absorption via the displacement of cholesterol from micelles in the intestine. Plant sterols and stanols have been shown to lower LDL-C by 10–14% (84,85), but they do not alter HDL-C or triglyceride levels (86).
Available data indicate that the maximum effect of stanols/sterols is seen at an intake of at least 2 g/day (2) taken on a daily basis. In addition to plant sterol/stanol supplements, generally available in a soft gel capsule form, many products, including margarines, dairy products, cereals/cereal bars and beverages, now include stanols/sterols and are available in grocery stores. As with nuts, patients should be encouraged to substitute these foods for other isocaloric foods in their diet to prevent excess calorie intake and subsequent weight gain. Plant stanols/sterols are generally well tolerated with no adverse events. Some research indicates, however, that a decline in serum carotenoid and fat soluble vitamins levels may be brought on by consuming stanols/sterols (87). Thus, patients should be encouraged to consume foods that are high in carotenoids, including fruits and vegetables with deep colors of red, yellow, orange and green, such as carrots, kale, collard greens, tomatoes, sweet potatoes, peaches, and apricots.
Oxidative stress is a putative cause of atherosclerotic disease. Therefore, research has been directed toward the potential role of antioxidants in reducing CHD risk (9) . At this time, however, there have been no clinical trials to strongly support the cardioprotective effects of antioxidants. Reports of the positive effects of antioxidants from foods and supplements on CHD have arisen from observational studies only. The most extensively studied antioxidants are vitamin C, E, b-carotene, coenzyme Q10, bioflavanoids, and selenium. For the time being, patients should not be encouraged to take in high levels of antioxidants in the form of supplements, due to available evidence from trials that they may, in fact, do more harm than good. b-Carotene supplementation has been associated with increased risk of lung cancer in smokers (88), whereas long-term vitamin E supplementation has been associated with increased risk for heart failure in patients with vascular disease or diabetes mellitus (89). Furthermore, a metaanalysis concluded that high doses of vitamin E may increase total mortality (90). It is therefore recommended that patients simply try to include in their diet more food sources of antioxidants, such as fruits, vegetables, and whole grains. Although antioxidant vitamins may theoretically be beneficial for reducing the risk of CHD, more conclusive data from large controlled clinical trials are clearly needed.
The current body of research on folate and other vitamins of the B complex is similarly inconclusive. There has been strong evidence showing a correlation between elevated homocysteine levels and CVD risk (91), but there is insufﬁcient evidence to suggest that supplementation with folic acid, B6, and B12 plays an important role in reduction of CVD risk. More research is necessary in this area before supplementation of these vitamins is recommended for CVD risk reduction.
Obesity is clearly a risk factor for CHD and has been consistently shown to influence several CHD factors, namely blood LDL-C, triglyceride, and HDL-C levels, hypertension, and insulin resistance (92). Weight gain prevention is obviously the most desirable method for avoiding the excess risk of CHD associated with obesity, but for the majority of CHD patients, weight gain has already occurred and weight reduction and/or maintenance becomes the greatest obstacle. For patients who are already overweight or obese, the initial goal of weight loss therapy is to reduce body weight by ~10% from baseline. If this goal is achieved, further weight loss can be attempted, as indicated through further evaluation. A reasonable time line for a 10% reduction in body weight is 6 months. For overweight patients with BMIs in the typical range of 25–35 kg/m2, a decrease of 300–500 kcal/day will result in weight loss of about 0.5–1 lb/week and a 10% loss in 6 months. For more severely obese patients with BMIs > 35 kg/m2, deficits of about 500–1,000 kcal/day will lead to weight loss of ~1–2 lbs/week and a 10% weight loss in 6 months (7) . Definitions of success for a weight management program are patient-specific. Reduction of risk factors, even if weight is not lost, is considered “success” from a health(Buy now from http://www.drugswell.com) point of view. For patients unable to achieve significant weight reduction, prevention of further weight gain is an important goal; such patients may also be encouraged to participate in a weight management program. For patients resistant to weight reduction through dietary intervention alone, a concomitant pharmacotherapy and physical activity program may help to achieve the weight loss target, as indicated (see Chap. 16 ).
9. PHYSICAL ACTIVITY
Observational and randomized controlled clinical studies consistently show that physical activity is effective in both primary and secondary prevention of CHD. The effects of physical activity on CHD risk reduction are due, in part, to favorable effects on blood pressure, triglyceride levels, HDL-C levels, insulin sensitivity, glucose tolerance, and body weight. Physical activity and weight loss decrease LDL-C levels and lessen the reduction in HDL-C that often occurs with a diet that is low in total fat and SFA (93).
The American College of Sports Medicine and the American Heart Association recommend that people should get a minimum of 30 min of moderate-intensity aerobic physical activity for 5 days each week or a minimum of 20 min of vigorous-intensity aerobic activity for 3 days each week (94). Moderate physical activity is described as walking, climbing stairs, gardening, yard work, moderate-to-heavy housework, dancing, and exercise at home. Patients who stress that they are unable to ﬁnd time for daily activity should be encouraged to accumulate exercise minutes in shorter bouts of 10 min at a time throughout the day to reach their 30 min goal. Although existing research evidence is not conclusive, a summary of the experimental ﬁndings suggests that moderate-intensity physical activity in shorter bouts (usually lasting 10 min) that is accumulated toward the 30-min minimum can be as effective as single, longer exercise sessions in reducing risk factors for chronic disease (94). In patients with cardiovascular risk factors, individually tailored prescriptions must take into account the patient’s main metabolic defect. To modify the lipid proﬁle, exercise should be aerobic and of moderate intensity, with an energy expenditure greater than 300 kcal (equivalent to a weekly energy expenditure of at least 2,000 kcal). With regard to insulin sensitivity, power training is just as effective as aerobic exercise, and if the prime objective is to lose weight, prolonged, mild-intensity work should be performed daily if possible (95).
Moreover, special care must be taken during the assessment of patients with chronic disease. Once the patient has been stabilized after an acute coronary event, physical activity, along with psychological support, educational and preventive strategies, should be included in rehabilitative therapy. It has been shown that to improve cardiovascular adaptability to effort, the intensity of physical exercise must be 60–75% VO 2 max (determined during initial cardiopulmonary evaluation), which corresponds to a heart rate between 70 and 85% of that reached at the peak of exercise. Nevertheless, if the intensity of effort exceeds 80% of the maximum aerobic capacity, the risk of cardiovascular complications appears to outweigh the beneﬁ ts (95). Patients with CHD should be monitored closely during physiologic testing. The appraiser must have a clear understanding of the effects of the patient’s clinical status and medications on the physiologic response to exercise.
Low-intensity exercise is generally better accepted by people naive to exercise training, those who are extremely deconditioned (“out of shape”), and older people. Low-intensity exercise may result in an improvement in health(Buy now from http://www.drugswell.com) status with little or no change in physical ﬁtness. Indeed, light or moderate activity is associated with a reduced risk of death from any cause among men with established CHD. Furthermore, regular walking or moderate to heavy gardening has been shown to be sufﬁcient in achieving health(Buy now from http://www.drugswell.com) beneﬁ ts. Individuals with low baseline ﬁtness levels can achieve signiﬁcant improvements in physical ﬁ tness with a lower training intensity (e.g., 40–50% of heart rate reserve) than that needed by individuals with a higher baseline ﬁtness level, whereas the latter would need a greater level of exercise intensity to achieve further improvements in ﬁ tness. Deconditioned individuals may improve their physical ﬁtness with as little as two exercise sessions per week. Others have shown an improvement in aerobic ﬁ tness with exercise intensities as low as 30% of heart rate reserve in sedentary people. Long-term adherence to this form of exercise may be poor, however, and the risk of musculoskeletal injury high, especially in people unaccustomed to exercise (96).
10. NUTRITION COUNSELING AND ADHERENCE ISSUES IN PATIENTS WITH CVD
Implementation and maintenance of dietary and physical activity changes is of major importance. Evidence suggests that sustained improvements in diet composition require individualized and reinforced counseling in patients with CHD (97). Dietitians may be better able to help patients lower their total and LDL-C levels through nutrition counseling in the short to medium term (98,99). This may be due to the greater amount of time devoted to advising patients. Others have shown that the effects of a dietitian-based program for hyperlipidemia were additive to those observed after a physician-delivered intervention in the US health(Buy now from http://www.drugswell.com)care system (100).
Individualized interventions based on the stages of change and behavioral techniques are more effective in inducing dietary changes and some improvements in CHD risk factors, compared with the more traditional methods of provision of information and exhortation (101–103). Still, corresponding changes in biochemical indexes are not always present. Stage-matched nutrition counseling promotes progress through stages of change (104) and future research should focus on feasible ways to keep patients in the postpreparation stage.
The U.S. Preventive Services Task Force recommends intensive behavioral dietary counseling for adult patients with hyperlipidemia and other known risk factors for cardiovascular disease, by primary care clinicians or by referral to other specialists and/or nutritionists/dietitians (105). Following these recommendations, effective interventions should combine nutrition education with behavior-oriented counseling to help patients acquire the skills, motivation, and support they need to alter their daily eating patterns and food preparation practices. Examples of behavior-oriented counseling interventions include teaching self-monitoring, helping patients to set their own goals and seek social support, providing guidance in shopping and food preparation, training patients to overcome everyday barriers in making appropriate food choices, and preventing relapse. In general, these interventions can be described with reference to the 5-A behavioral counseling framework (adapted from tobacco cessation interventions in clinical care) (106):
Nutrition intervention in CVD represents an evolving scientific area, which expands from the effects of single nutrients (e.g., fatty acids, fiber) to those of food groups (e.g., fruits, vegetables, whole grains) and dietary patterns. The latter, as a holistic approach, gains continuously more attention and has resulted in scientific data supporting the beneficial role of Mediterranean and DASH diets on CVD prevention and treatment. Furthermore, individuals with CVD should also be given individualized guidance to achieve a health(Buy now from http://www.drugswell.com)y body weight change (at a first stage to reduce their body weight by ~ 10% from baseline) and engage in a minimum of 30 min of moderate-intensity aerobic physical activity for 5 days a week. Nutrition and other health(Buy now from http://www.drugswell.com)-related professionals should implement effective interventions combining education with behavior-oriented counseling, focusing on motivating and supporting patients to change their lifestyle habits.
Key Words: Medical nutrition therapy , Diabetes Obesity
From: Nutrition and health(Buy now from http://www.drugswell.com): Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_13, © Humana Press, a part of Springer Science + Business Media, LLC 2009
Type 1 diabetes is an autoimmune disease with genetic and environmental factors influencing its development (2). Prospective studies show that islet cell autoimmunity can begin early in life and that dietary factors can be possible triggers or protective factors. In particular, a short breastfeeding period and an early introduction of customary formulas based on cow’s milk to infant’s diet have been associated with an increased risk of diabetes in several ecological and epidemiological studies (3–7). Although both animal and immunological studies in man further supported the cow’s milk hypothesis (8) , the evidence cannot be regarded as fully conclusive so far. Two metaanalyses led to inconsistent results either ascribing the observed weak associations to causal relationships (7) or to methodological shortcomings of the studies (9). In a recently published nationwide case–control study by Rosenbauer et al. (10) in Germany, short breastfeeding and early introduction of formula feeding (before vs. fifth month or later) were risk factors of the development of type 1 diabetes in preschool age children [adjusted odd ratios:
1.31 (1.01–1.69) and 1.34 (1.03–1.74), respectively]. In addition, late introduction of solid food (i.e., after the fourth month of age) was associated with reduced diabetes risk. Hopefully, in the near future, a worldwide, prospective, randomized, double-blinded intervention study (Trial to Reduce Diabetes in Genetically at Risk, TRIGR), including 2,160 newborns who carry high-risk HLA alleles and have first degree relative with type 1 diabetes will definitively answer the question of whether avoiding cow’s milk protein in the first 6–8 months of life will reduce the appearance of multiple diabetes-related autoantibodies before the age of 6 years or the development of type 1 diabetes up to the age of 10 years (11). The 6-year autoantibody results will be available in 2012 and the type 1 diabetes in 2016.
Early introduction of gluten, a wheat protein, in baby’s diet is also thought to contribute as a trigger of the autoimmune process leading to destruction of pancreatic beta cells. In animal studies, elimination of this protein from the diet led to signiﬁcant reduction of diabetes autoimmunity (12). Since enteral permeability for macromolecules is increased during the ﬁrst months of life, it is possible that early introduction of nutrients may lead to sensitization against several nutritional parameters. Increased enteral permeability has been already described in patients with type 1 diabetes (13). Furthermore according to other theories, nutritional parameters like gliadin, a protein fraction of gluten, may elicit an inﬂammatory process in gut mucosa leading to an abnormal permeability and facilitating the exposure of the immune system to potential diabetogenic agents (14) . The effects of the elimination of gluten from the diet of children with a ﬁrst degree relative with type 1 diabetes during the ﬁrst year of life have been studied in an interventional prospective trial since 2001 (15). Whether this intervention can postpone or even avoid the development of diabetes-related autoimmunity or even clinical diabetes in this population will be shown in the near future, since the ﬁrst results of the BABYDIÄT Study are expected in 2008.
Vitamin D (1,25 dihydrocholecalciferol) has been discussed as a protective factor for the development of several diseases like type 1 diabetes, multiple sclerosis, rheumatic arthritis, hyperthyroidism, and Hashimoto thyroiditis (16) due to its immunomodulating action. Saggese et al. showed that vitamin D has an immunosuppressive action with in vitro suppression of proliferative T lymphocytes and inﬂuences on the production of cytokine proﬁ les (17). The EURODIAB Trial showed that vitamin D supplementation during the ﬁrst year of life was associated with reduced risk of type 1 diabetes (odds ratio [OR] 0.7, 95% conﬁdence intervals [95%-CI] 0.5–0.9) (18). Hypponen et al. found that the incidence of type 1 diabetes was signiﬁ cantly lower among subjects who received a regular daily dose of 2,000 units of vitamin D compared with those without supplementation (OR 0.1, 95%-CI 0.03–0.5) (19). Vitamin D supplementation seems to be a promising prevention for beta cell autoimmunity, and relative vitamin D deﬁ ciency is now recognized as a pandemic. Some experts suggest that both children and adults should take 800–1,000 IU of vitamin D per day from dietary and supplementatal sources, if sunlight cannot provide adequate Vitamin D levels, but this remains to be conclusively demonstrated. In summary, these recommendations have not yet been recognized nationally or globally as yet (20).
Fish oil contains not only vitamin D but also polyunsaturated fatty acids (PUFA), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Long-chain n-3 fatty acids are incorporated into cell membranes and have antiinﬂ ammatory properties that may be relevant to the prevention of type 1 diabetes, such as decreased expression of HLA class II molecules on activated human monocytes (21) and reduced expression of interleukin 1β. These data suggest that the antiinﬂ ammatory n-3 fatty acids such as DHA and EPA may reduce the risk of disease development (22). The levels of vitamin D and PUFA in newborns depend on the nutritional state of the mother during gestation (23,24). In a Norwegian study, children from mothers with fish oil supplementation during pregnancy had a lower risk of type 1 diabetes (OR 0.3, 95%-CI 0.1–0.8) (25).
In summary, although there is promising evidence that nutrition in early stages of life may influence the initiation of beta cell autoimmunity in genetically predisposed individuals, there is currently no conclusive data allowing particular recommendations for nutritional interventions or vitamin supplementation to prevent the development of type 1 diabetes later in life. Until the results of the large prospective interventional studies are known, generally accepted guidelines for the nutrition of neonates and infants suggesting exclusive breastfeeding for the ﬁrst 4–6 months of life are highly recommended.
The first nutrition priority for individuals requiring insulin therapy is to integrate an insulin regimen into their lifestyle. With the many insulin options now available, an appropriate insulin regimen can usually be developed to conform to an individual’s preferred meal routine, food choices, and physical activity pattern.
In general, the nutrition of children and adolescents with type 1 diabetes does not differ from that of their nondiabetic peers. Daily requirements of carbohydrates, fat, and proteins depend on age, gender, height, weight, levels of daily activity and particular living conditions such as climate and season. Energy and nutritional requirements including vitamins, minerals, and fluids show a higher inter and intraindividual variability in children and adolescents than in adults. Frequent change of energy and nutritional requirements accompanied by frequent changing of food types characterize the nutritional habits of young people. Personal preferences and different eating habits of the family serve to increase the variability of nutrition among young people with type 1 diabetes. Once overweight and/or obesity are absent, one can assume that the physiological regulation of appetite guarantees balanced nutritional and energy requirements of the growing child. For this reason, nutritional guidelines can only provide an orientation aid for pediatricians and pediatric diabetologists. Interestingly, the definition of overweight and obesity in childhood varies between the continents. Thus, in the US overweight and obesity are defined as body mass index (BMI) exceeding the 85th and 95th percentiles of the US CDC 2000 reference, in the UK the definitions use the 91st and 98th percentiles of the British 1990 reference, in Germany the 90th and 97th percentiles, respectively (26–28).
The oldest and simplest way to calculate energy needs (in kcal) of children is the one proposed by Priscilla White according to following formula (29):
age (years) ´ 100 + 1,000 = daily energy requirements (kcal).
The recommended amount of carbohydrates in daily energy intake varies worldwide. In some countries, it is between 60 and 70%, while in others, such as Europe, it is between 45 and 60%. The International Society for Pediatric and Adolescent Diabetes (ISPAD) recommends that carbohydrates should cover at least 50% of daily energy intake (Table 1 ) (30). Studies have shown that the higher the percentage of carbohydrates, the lower the consumption of fat.
Daily consumption of ﬁber is recommended to be around 14 g/1,000 kcal. In other words, for children older than 2 years, daily needs of ﬁber (in g) are equal with child’s age (in years) plus ﬁ ve (31).
Fat consumption should not exceed 35% of daily energy intake in children older than 4 years. To prevent the development of cardiovascular diseases (CVDs) later in life, it is important to avoid triglycerides with saturated (animal fat) and trans-unsaturated fatty acids (cookies, chocolate, sweets). Otherwise, the consumption of polyunsaturated fatty acids (PUFA) of herbal or vegetarian origin or omega-3-fatty acids is recommended (Table 1 ) (31).
The calculation of daily protein needs depends on age, gender, and stage of the somatic development of the child. It varies between 1.2 and 0.8 g per kg body weight per day. This corresponds to 10–15% of the daily energy intake (Table 1 ) (31).
Distribution of Elementary Nutrients in the Daily Energy Intake in Children and Adolescents (30)
Carbohydrates >50% Prefer complex, non-afﬁ ne, ﬁ ber-rich carbohydrates Moderate saccharose intake
Fat 30–35% Less than 10% saturated fatty acids Less than 10% polyunsaturated fatty acids More than 10% monounsaturated fatty acids
Protein 10–15% Less protein with increasing age
Children and adolescents have higher daily ﬂuid requirements compared with adults. Daily ﬂuid intake corresponds to 10–15% of child’s body weight, whereas this is only 2–4% in adults. Usually food items consumed by children are more rich in ﬂuids than those of adults: solid foods contain ∼60–70% water, fruits and vegetable almost 90%.
In summary, the following three rules for food consumption could beneﬁ t everybody in choosing health(Buy now from http://www.drugswell.com)y food for children and adolescents:
For the education of nonobese patients with type 1 diabetes, visual aids like the food guide pyramid by the US health(Buy now from http://www.drugswell.com) Department and Human Services are used (Fig. 1 ). Food guide pyramids (such as in Fig. 1 and/or the newer pyramids, see in appendix and at http://mypyramid.com ) suggest optimal nutrition guidelines for each food category, using a mnemonic graphic of a pyramid with horizontal dividing lines to represent suggested percentages of the daily intake for each food group. For younger children, age-adjusted food pyramids such as the aid infodienst-pyramid are incorporated into their training programs (Fig. 2 ). This uses the trafﬁ c light system to indicate recommended consumption of nutrients (green = abundant, yellow = moderate, red = thriftily), modules of servings equal to child’s hand size and the 6-5-4-3-2-1-rule (32).
Fig. 1. A recent food guide pyramid by the US health(Buy now from http://www.drugswell.com) Department and Human Services. The food guide pyramids suggest optimal nutrition guidelines for each food category, per day, using a mnemonic graphic of a pyramid with horizontal dividing lines to represent suggested percentages of the daily diet for each food group. This food guide pyramid was recently replaced with the new food guide pyramid (see appendix and http://mypyramid.com).
Fig. 2. German example of food pyramid for children using the trafﬁc light system to indicate recommended consume of nutrients (green = abundant, yellow = moderate, red = thriftily), modules of servings equal to child’s hand size and the 6-5-4-3-2-1-rule (32) . Copyright: aid infodienst.
For individuals receiving “conventional therapy,” which is defined as prebreakfast and presupper injections of short and intermediate acting insulin, food should be kept consistent in terms of timing and amount. For those using “intensive therapy,” which consists of three or more injections of insulin or use of an insulin pump, individuals should be taught to adjust their meal and snack at the times of insulin doses based on their total carbohydrate content.
Current knowledge about the content of carbohydrates in the daily nutrition of patients with type 1 diabetes suggests using different goals depending on the type of treatment. Patients treated with conventional therapy must calculate the amount of carbohydrate to avoid decreases of blood glucose levels after insulin injection. Patients treated with intensiﬁed insulin regimes should be aware of the amount of carbohydrate in their food in order to calculate the amount of insulin they need to avoid nonphysiological increases of postprandial blood glucose. Patients treated with a continuous subcutaneous insulin infusion (CSII) pump system have the possibility of using three different kinds of boluses to regulate their postprandial glycemic proﬁles: normal bolus delivering insulin rapidly as a shot, square-wave bolus delivering insulin for an extended period of time (h), and dual-wave bolus in which a certain amount of insulin is released immediately and the rest over an extended period of time (33). Use of dual-wave bolus may be more effective than the use of a normal bolus to control postprandial glucose proﬁle after meals rich in carbohydrates and fat (33).
To achieve optimal glycemic proﬁles during conventional insulin treatment, food intake has to be distributed in frequent and small meals. A dietary plan consists mostly of three main meals (breakfast, lunch, and dinner), two snacks in between and one more before bedtime. During intensiﬁ ed insulin treatment with differentiated basal and prandial insulin substitution, however, patients are very ﬂexible in their daily routine. They can decide when and how much they want to eat. The most important prerequisite is their ability to know and estimate the nutrient content of meals to calculate the amount of insulin they need for the planned meal.
Several methods can be used to estimate the nutrient content of meals, including carbohydrate counting, the exchange system, and experience-based estimation. The DAFNE (Dose Adjustment for Normal Eating) study demonstrated that patients can learn how to use glucose testing to better match insulin to carbohydrate intake (34,35). Improvement in HbA1c without a signiﬁcant increase in severe hypoglycemia was demonstrated, as were positive effects on quality of life, satisfaction with treatment, and psychological well-being, even though increases in the number of insulin injections and blood glucose tests were necessary.
For planned exercise, reduction in insulin dosage is the preferred method to prevent hypoglycemia. For unplanned exercise, intake of additional carbohydrate is usually needed. Moderate-intensity exercise increases glucose utilization by 2–3 mg/kg/min above usual requirements (1). For that reason, high to normal levels of blood glucose between 150 and 180 mg/dL are the aim before physical activities. Patients on insulin treatment are educated to eat 10–15 g of carbohydrates before sports if blood glucose levels are below 150 mg/dL.
MNT has been reported to decrease HbA1c by ∼1% in type 1 diabetic patients (36).
For individuals at risk for diabetes or who have prediabetes, the goals of MNT are to decrease diabetes and CVD risk by encouraging moderate weight loss maintained by health(Buy now from http://www.drugswell.com)y food choices and physical activity (36). Evidence from epidemiologic studies suggests that certain individual foods and dietary patterns may help prevent type 2 diabetes. There is also accumulating evidence from clinical trials in favor of lifestyle changes that incorporate moderate weight loss and increasing leisure time physical activity. Use of certain medications could also achieve similar goals but use of medications for this purpose is not considered cost-effective and is not currently recommended.
Epidemiologic evidence suggests that certain dietary components and overall diet-quality may reduce the risk of developing type 2 diabetes. An evaluation of available observational studies found strong evidence that a diet high in soluble or insoluble ﬁ ber can reduce the risk of type 2 diabetes. Somewhat weaker evidence suggests an association between diets low in glycemic index and reduced risk of disease (37). Prospective cohort studies also suggest that diets higher in whole grains, cereal ﬁber, and magnesium may lower the risk of type 2 diabetes (38). Certain individual foods such as coffee (39,40) and nuts (41) have also been associated with reduced diabetes risk in cohort studies, while increased consumption of meat (42–44) and sugar-sweetened beverages (45) may increase the risk. Interestingly, our own studies have recently demonstrated that these beneﬁcial diets also increase circulating levels of adiponectin, an adipocyte-secreted hormone and levels of which are a strong inverse predictor of insulin resistance and diabetes (46–48). Prospective investigations also suggest that certain health(Buy now from http://www.drugswell.com)y dietary patterns may help prevent diabetes. In an analysis of 80,029 women from the Nurses’ health(Buy now from http://www.drugswell.com) Study, those with the highest adherence to a health(Buy now from http://www.drugswell.com)y diet, as measured by the Alternative health(Buy now from http://www.drugswell.com)y Eating Index, had lower risk of type 2 diabetes during 18 years of follow-up (RR = 0.64, 95% CI 0.58–0.71) (49) . Beneﬁts of many individual dietary components in reducing the risk of diabetes have yet to be conﬁrmed by interventional studies.
Prospective studies suggest that even modest sustained weight loss is associated with dramatically reduced risk of type 2 diabetes (50,51). Leisure time physical activity has also been associated with lower risk of developing diabetes mellitus in cohort studies (52–54), including moderate activities such as walking (55). Recent interventional studies have sought to determine whether a combined program of moderate weight loss and physical activity can prevent type 2 diabetes among those at high risk. The Diabetes Prevention Program (56) randomized trial compared the effects of placebo, metformin, and intensive lifestyle intervention on prevention of type 2 diabetes in 3,234 subjects with impaired glucose tolerance. The goal of the lifestyle-modiﬁ cation intervention was to achieve 7% weight loss through a low-calorie, low-fat diet and to engage in at least 150 min of physical activity per week. After an average follow-up of
2.8 years, the incidence rate of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. Incidence of type 2 diabetes was reduced by 58% in the lifestyle group and by 31% in the metformin group compared with placebo (56). The Finnish Diabetes Prevention Study also found that a similar intensive lifestyle intervention involving dietary counseling and increased physical activity resulted in improved glucose levels, lipid markers, and BMI after 3 years compared with controls (57). Extended follow-up of this study found that those who participated in the lifestyle intervention continued to have reduced risk of type 2 diabetes for years after the intervention ended (58).
There are several goals of MNT for individuals with diabetes, as recommended by the American Diabetes Association (ADA). The first goal is for the patient to achieve and maintain blood glucose levels in the normal range or as close to normal as is safely possible (36). The ADA guidelines for normal blood glucose levels are as follows: Hemoglobin A1c (HbA1c) <6.5%, preprandial plasma glucose <110 mg/dL, and postprandial glucose <140 mg/dL. Another aim of MNT is to aid patients with diabetes in achieving and maintaining a lipid and lipoprotein profile that reduces their risk for vascular disease (36). This includes the maintenance of optimal LDL-C levels, HDL-C levels, triglycerides, and total cholesterol. Effective MNT should also allow patients to achieve blood pressure levels in the normal range or as close to normal as is safely possible and to achieve a health(Buy now from http://www.drugswell.com)y BMI.
After diagnosis, medical nutrition therapists can use the initial consultation framework provided by the American Dietetic Associations Care Manual (59) in developing their initial care plan. Although every patient interaction will be different and the care plan will undoubtedly be tailored to reﬂ ect this, the framework can be helpful in providing consistency of care to all patients. When working with a patient who has been recently diagnosed with diabetes, the framework recommends educating the patient on basic nutrition, diabetes nutrition guidelines, and beginning strategies for altering eating patterns. Continuing self-management counseling includes both management skills and lifestyle changes. Flexibility in food planning should always be addressed. Topics emphasized or chosen are based on the following factors related to the individual (59): choice, lifestyle, levels of nutrition knowledge, and experience in planning, purchasing, and preparing foods and meals. After the initial visit, it is important to establish a timeline for follow-up, which helps to identify expected outcomes (e.g., preprandial and postprandial blood glucose goals) and determine response to and effectiveness of nutritional care.
Patients with diabetes cannot rely on counting calories alone since carbohydrates are the major determinant of postprandial glucose levels. The amount of carbohydrate ingested is usually the primary determinant of postprandial response, but the type of carbohydrate can also have an effect. Patients may have the impression that there is a diabetic diet and that once type 2 diabetes is diagnosed all sugar(s) must be avoided. In reality, people with diabetes can eat the same foods as those who do not have the disease, but they must be sure to match insulin and insulin secretagogues to the carbohydrate content of their meals. Patients can be educated to do this in a variety of ways including the use of exchange lists and carbohydrate counting, the most widely used method. In educating a patient on carbohydrate counting, the ﬁrst step is to teach the patient which foods contain carbohydrates (starches, fruits, starchy vegetables, milk, and sweets). For diabetes meal planning, one serving of a food with carbohydrates has about 15 g of carbohydrates. The number of grams of carbohydrates that a person can eat each day or at each meal is determined by factors such as the patient’s weight, whether or not a calorie-restricted diet to induce weight loss is necessary, timing, and type of physical activity, and medications. For many adults, eating 3–5 servings of carbohydrate foods at each meal and one or two carbohydrate servings for each snack is effective. A meal plan that incorporates carbohydrate counting would highlight the number of servings to select per meal to avoid exceeding the amount of grams of carbohydrates per meal. This structure and consistency is a major tool in maintaining glucose control. Research has not demonstrated that one method of assessing the relationship between carbohydrate intake and blood glucose response is better than another. However, it is very important that individuals adhere to a system that they understand and which they can follow consistently – whether it is carbohydrate counting, the exchange system, or monitoring carbohydrate using experienced-based estimation.
In the US, the recommended daily allowance for carbohydrates is 130 g/day. Since there is no data regarding very low intake of carbohydrates speciﬁcally in patients with diabetes, diets restricting total carbohydrates to <130 g/day are not recommended in the management of diabetes. High-carbohydrate diets (55% of total energy from carbohydrates) increase postprandial plasma glucose, insulin, and triglycerides when compared with high-monounsaturated fat diets (60), but diets restricting carbohydrates to <130 g/ day have not been proven to be sustainable.
Individuals with diabetes should be encouraged to consume vegetables, fruits, legumes, and whole and minimally processed grains as their major source of carbohydrates. Reﬁned carbohydrates or processed grains and starchy foods (especially pasta, white bread, low-ﬁber cereal, and white potatoes) are not recommended and should be consumed in limited quantities.
Current guidelines recommend at least 14 g/1,000 kcal of ﬁber per day for a health(Buy now from http://www.drugswell.com)y individual. For type 2 diabetics, available evidence suggests that consuming a high-ﬁ ber diet of at least 50 g of ﬁ ber per day leads to reduction in glycemia, hyperinsulinemia, and lipemia by slowing down the digestion of carbohydrates (61). However, a goal of 50 g/day may not be realistic for the majority of the population due to barriers including taste and gastrointestinal side effects. These side effects can be diminished by increasing ﬁ ber in the diet gradually ( ∼3–5 g/day) until the recommended goal is met and by increasing ﬂ uid intake. Increased ﬁ ber intake can be achieved by choosing a variety of ﬁ ber-containing foods such as legumes, ﬁber-rich cereals (>5 g ﬁ ber/serving), fruits, vegetables, and whole grain products, all of which provide vitamins, minerals, and other substances important for good health(Buy now from http://www.drugswell.com).
With respect to dietary fat, the primary goal for individuals with diabetes is to limit saturated fatty acids, trans-fatty acids, and cholesterol intake to reduce the risk for CVD. Saturated and trans-fatty acids are the principal dietary determinants of plasma LDL cholesterol. In nondiabetic individuals, reducing saturated and trans-fatty acids and cholesterol intakes decreases plasma total and LDL cholesterol (62). Saturated and trans-fat should make up <10% (59) of caloric intake, but the most current recommendations state that <7% of the diet should consist of saturated fat alone (36) . Foods high in saturated fat, including beef, pork, lamb, and high fat dairy products (e.g., cream cheese, whole milk, or full fat cheese) are not recommended and should be consumed only in small amounts. Foods high in trans-fats (e.g., fast foods, commercially baked goods, some margarines) should also be avoided.
Fat restriction to <30% of the diet can decrease total and LDL cholesterol as well as obesity (63,64). However, it is important to notice when patients consuming a low fat diet begin to supplement their diet with a greater proportion of carbohydrates. High carbohydrate intake leads to increased postprandial blood glucose and increased fasting triglycerides (65). Because of these nuances, it is very important to individualize fat and carbohydrate intake for optimal results in a particular patient. If a low-fat diet is not producing desired outcomes, it may be necessary to shift ratios and evaluate caloric intake (66).
Certain types of fat may have beneﬁcial effects for individuals with diabetes. In those individuals who are already hyperlipidemic, studies have shown that mono and polyunsaturated fats have beneﬁcial effects on lipid proﬁ les (67). Very-long-chain n-3 polyunsaturated fatty acid supplements have been shown to lower plasma triglyceride levels in individuals with type 2 diabetes who are hypertriglyceridemic. Although the accompanying small rise in plasma LDL cholesterol is of concern, an increase in HDL cholesterol may offset this concern (68). Recommended fats such as olive oil and walnuts, which have high mono and polyunsaturated fats, should displace high saturated fat and trans fat-containing foods from the diet. Other recommended mono and polyunsaturated fats include canola oil, nuts/ seeds, and ﬁsh, particularly those high in omega-3 fatty acids. For instance, oily ﬁ sh (e.g., salmon, herring, trout, sardines, fresh tuna) two times a week is an ample source of omega 3 fatty acids. More details about supplemental dose, if taken as a pill, can be found in the relevant chapter of this book.
Plant sterol and stanol esters block the intestinal absorption of dietary and biliary cholesterol. In the general public and in individuals with type 2 diabetes (21), intake of 2 g/day plant sterols and stanols has been shown to lower plasma total and LDL cholesterol (36).
Currently, there is a wide range of new food products that contain plant sterols. Because these are fats which carry 9 cal/g, it should be advised that, like mono and polyunsaturated fats, these should be avoided to prevent weight gain. Supplements are also available.
Individuals with diabetes have the same needs for protein as those who do not have diabetes. The Dietary Reference Intakes’ acceptable macronutrient distribution range for protein is 10–35% of energy intake, with 15% being the average adult intake in the US and Canada (69). There are some special considerations related to protein for anyone that shows signs of kidney disease. Protein intake for those with renal problems will need to be modiﬁed. A diet that includes a lower amount of protein is recommended for these patients, but it is important to emphasize that protein does not need to be lowered to a point that may jeopardize the overall nutrition quality of their diet, and thus a nephrologist should be consulted before making any dietary changes. Although there is no evidence that strongly supports reduction of protein intake in diabetics without renal complications, studies have shown that in subjects with diabetes and microalbuminuria, reduction of protein intake to 0.8–1.0 g/kg/day decreased urinary albumin excretion rate and decreased rate of decline in glomerular ﬁltration. This requires patients to limit meat, ﬁsh, and poultry intake to 3–5 oz/day, which may be difﬁcult for some patients to achieve at ﬁ rst. Because individuals with diabetes are at an increased risk for cardiac disease, it is suggested that they ﬁrst try to decrease protein in their diet from animal sources high in saturated fats. Favorable protein sources include ﬁsh, skinless poultry, nonfat or low-fat dairy, legumes, tofu, and tempeh. There is no evidence at this time to suggest that vegetable proteins have any nephrotoxic effects and these do not need to be limited.
High-protein diets are not recommended as a method for weight loss at this time. Although high protein diets may be effective at producing short-term weight loss results and improved blood glucose control, the long-term effects of protein intake >20% of calories on diabetes management and its complications, including effects on the kidneys, remain unknown.
Alternative sweeteners may be used to reduce sugar intake for diabetics. Sorbitol, mannitol, and fructose are commonly used sweeteners that have a lower glycemic effect than glucose or sucrose. However, they do contain the same amount of calories as glucose and sucrose (4 cal/g), a fact that is usually forgotten. Sorbitol and mannitol may cause bloating and diarrhea when >30 g/day are consumed (66). Though fructose produces a lower postprandial glucose response when it replaces sucrose or starch in the diet, there are concerns that it may adversely affect the lipid proﬁ le. Reduced calorie sweeteners approved by the FDA include sugar alcohols such as erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, tagatose, and hydrogenated starch hydrolysates. Sugar alcohols contain about 2 cal/g. When calculating carbohydrate content of foods containing sugar alcohols, subtraction of half the sugar alcohol grams from total carbohydrate grams is appropriate. There is no evidence at this time to suggest that the amounts of sugar alcohols likely to be consumed will reduce glycemia, energy intake, or weight. The use of sugar alcohols appears to be safe; however, like sorbitol and mannitol, they may cause gastrointestinal upset. The FDA has approved ﬁ ve nonnutritive sweeteners for use in the US. These are acesulfame potassium, aspartame, neotame, saccharin, and sucralose, compounds that are 200 times sweeter than sugar, allowing their use in very small quantities. This makes them beneﬁcial to diabetics because they add virtually no caloric or nutritional value to food (65). However, they may be used in foods that contain other sources of carbohydrates and calories such as ice cream, cookies, and puddings. Thus, not only the energy these compounds provide but total energy must be taken into account (1).
Complete abstinence from alcohol is not necessary for diabetics. If alcohol is consumed, intake should be consistent with the 2005 USDA Dietary Guidelines for Americans, which recommend no more than one drink per day for women and two drinks per day for men. For education purposes, one alcohol containing beverage is deﬁned as 12 oz beer, 5 oz wine, or 1.5 oz distilled spirits. Each contains >15 g alcohol. Alcohol itself has minimal effects on plasma glucose and serum insulin levels. However, when coingested with carbohydrates, blood glucose may rise. Diabetic patients should note that, when using insulin or insulin secretagogues, alcohol should be consumed with food to avoid hypoglycemia (1,66). Alcohol should be avoided in patients with hypertriglyceridemia, however, because it causes increased elevation in postprandial triglyceride levels (65).
Individuals with diabetes should be aware of the importance of acquiring daily vitamin and mineral requirements from natural food sources and a balanced diet. In select groups such as the elderly, pregnant, or lactating women, strict vegetarians, or those on calorie-restricted diets, a multivitamin supplement may be needed (66). Uncontrolled diabetes is often associated with micronutrient deﬁciencies. With regard to antioxidants, there is no clear evidence that they improve glycemic control and long-term complications of diabetes. In contrast, there is some evidence of possible harm in taking high doses of antioxidant supplements such as vitamin E and carotene. Finally, there is no evidence at this time that antioxidant supplementation has any role in the prevention of CVD (1).
Chromium, potassium, magnesium, and possibly zinc deﬁciency may aggravate carbohydrate intolerance. Serum levels of potassium and magnesium can be checked and should be replaced as needed, but there is no clear evidence that zinc or chromium replacement beneﬁt those with diabetes, although deﬁnitive trials have yet to be performed. Thus, it is uncertain whether herbal or vitamin supplementation is beneﬁ cial to individuals with diabetes unless there is an established micronutrient deﬁ ciency. Because commercially available products are not standardized, vary in the content of active ingredients, and have the potential to interact with other medications, it is important that health(Buy now from http://www.drugswell.com) care providers are aware of the use of these products by their diabetic patients. The following popular herbals have been shown to lower blood glucose (an effect which may potentially interact with blood glucose lowering medications): Ginseng (Panax ginseng); Fenugreek (Trigonella foenum-graecum) ; Bitter Melon ( Momordica charantia); Garlic (Allium sativum). Their intake should also be taken under consideration by practicing physicians.
Exercise increases both insulin sensitivity and uptake in skeletal musc