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 Nutrition and
Cardiometabolic Health
 Nutrition and
Cardiometabolic Health

Edited by
Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray,
and Ronald M. Krauss
CRC Press
Taylor & Francis Group
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Library of Congress Cataloging-in-Publication Data

Names: Bergeron, Nathalie, editor. | Siri-Tarino, Patty W., editor. | Bray,

George A., editor. | Krauss, Ronald M., editor.
Title: Nutrition and cardiometabolic health / [edited by] Nathalie Bergeron,
Patty W. Siri-Tarino, George A. Bray, and Ronald M. Krauss.
Description: Boca Raton : Taylor & Francis, 2017. | Includes bibliographical
references.
Identifiers: LCCN 2017020806 | ISBN 9781498704267 (hardback : alk. paper)
Subjects: | MESH: Obesity, Metabolically Benign--diet therapy |
Cardiovascular Diseases--prevention & control | Risk Factors | Nutrition
Therapy—methods
Classification: LCC RC628 | NLM WD 210 | DDC 616.3/980654--dc23
LC record available at https://lccn.loc.gov/2017020806

Visit the Taylor & Francis Web site at

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Contents
Preface................................................................................................................................................ix
Editors................................................................................................................................................xi
Contributors......................................................................................................................................xv

Section I  Energy Balance, Adiposity, and

Cardiometabolic Health

Chapter 1 Regulation of Food Intake: The Gut–Brain Axis..........................................................3

Surya Panicker Rajeev, Ian W. Seetho, and John P. H. Wilding

Chapter 2 Overeating Behavior and Cardiometabolic Health: Mechanisms and Treatments......23

Ashley E. Mason and Frederick M. Hecht

Chapter 3 Energy Balance and Regulation of Body Weight: Are All Calories Equal?................51
Kevin D. Hall

Chapter 4 Diets for Weight Loss..................................................................................................61

George A. Bray and Patty W. Siri-Tarino

Chapter 5 Weight Loss by Surgical Intervention: Nutritional Considerations and Influence

on Health.....................................................................................................................77
Karim Kheniser and Sangeeta Kashyap

Chapter 6 Physical Activity and Cardiometabolic Health......................................................... 101

Andrea M. Brennan and Robert Ross

Chapter 7 Diet as a Potential Modulator of Body Fat Distribution........................................... 123

Sofia Laforest, Geneviève B. Marchand, and André Tchernof

Chapter 8 Nutritional Considerations for Cardiometabolic Health in Childhood and

Adolescent Obesity...................................................................................................149
Elizabeth Prout Parks, Jennifer Panganiban, Stephen R. Daniels,
and Julie Brothers

Chapter 9 Aging and Cardiovascular Disease: Lessons from Calorie Restriction.....................173

Jasper Most and Leanne M. Redman

v
vi Contents

Section II  Dietary Fats and Cardiometabolic Health

Chapter 10 Omega-3 and Omega-6 Fatty Acids: Roles in Cardiometabolic Disease..................193
William S. Harris

Chapter 11 Evolving Role of Saturated Fatty Acids....................................................................209

Patty W. Siri-Tarino and Ronald M. Krauss

Chapter 12 Effects of Dietary Trans Fatty Acids on Cardiovascular Risk...................................223

Ronald P. Mensink

Section III  D
 ietary Carbohydrates and
Cardiometabolic Health
Chapter 13 Epidemiologic and Mechanistic Studies of Sucrose and Fructose in Beverages
and Their Relation to Obesity and Cardiovascular Risk...........................................237
George A. Bray

Chapter 14 Effects and Mechanisms of Fructose-Containing Sugars in the Pathophysiology

of Metabolic Syndrome.............................................................................................251
Kimber L. Stanhope and Peter J. Havel

Chapter 15 Dietary Carbohydrate Restriction in the Management of NAFLD and

Metabolic Syndrome.................................................................................................275
Grace Marie Jones, Kathleen Mulligan, and Jean-Marc Schwarz

Chapter 16 Dietary Starches and Grains: Effects on Cardiometabolic Risk................................297

Nathalie Bergeron and Ronald M. Krauss

Section IV Dietary Protein and Cardiometabolic Health

Chapter 17 Interaction of Dietary Protein and Energy Balance...................................................317
Eveline A. Martens, Richard D. Mattes, and Margriet S. Westerterp-Plantenga

Chapter 18 A Protein-Centric Perspective for Skeletal Muscle Metabolism and

Cardiometabolic Health.............................................................................................333
Donald K. Layman

Chapter 19 Protein Sources, CVD, Type 2 Diabetes, and Total Mortality..................................349

Peter Clifton
Contents vii

Section V  ietary Food Groups, Patterns,

D
and Cardiometabolic Health

Chapter 20 Consumption of Foods, Food Groups, and Cardiometabolic Risk............................373

Edward Yu and Frank B. Hu

Chapter 21 Dietary Patterns and Cardiometabolic Disease.........................................................397

Elizabeth M. Cespedes Feliciano and Frank B. Hu

Chapter 22 The Mediterranean Diet to Prevent Type 2 Diabetes and Cardiovascular Disease...421
Michel de Lorgeril

Chapter 23 The DASH Diet.........................................................................................................431

Catherine M. Champagne

Chapter 24 Nut Consumption and Coronary Heart Disease (CHD) Risk and Mortality.............449
Christina Link, Alyssa Tindall, Jordi Salas-Salvadó, Caitlin Lynch, and
Penny Kris-Etherton

Chapter 25 Dairy Product Consumption, Dairy Fat, and Cardiometabolic Health......................481

Benoît Lamarche

Chapter 26 Paleolithic Diets........................................................................................................493

Staffan Lindeberg, Maelán Fontes Villalba, Pedro Carrera-Bastos, and
Lynda Frassetto

Chapter 27 Fasting Intermittently or Altering Meal Frequency: Effects on Plasma Lipids.........517

John F. Trepanowski and Krista A. Varady

Section VI  Other Nutritional Influences

of Cardiometabolic Health

Chapter 28 Early-Life Nutrition, Epigenetics, and Later Cardiometabolic Health.....................531

Mark H. Vickers, Clare M. Reynolds, and Clint Gray

Chapter 29 Gene–Diet Interactions..............................................................................................555

Silvia Berciano and Jose M. Ordovas
viii Contents

Chapter 30 Gut Microbiome: Its Relationship to Health and Its Modulation by Diet.................571
Brian J. Bennett and Katie A. Meyer

Chapter 31 Alcohol: Associations with Blood Lipids, Insulin Sensitivity, Diabetes,

Clotting, CVD, and Total Mortality..........................................................................593
Charlotte Holst and Janne Schurmann Tolstrup

Chapter 32 Endocrine Disrupting Chemicals, Obesogens, and the Obesity Epidemic............... 603
Raquel Chamorro-Garcia and Bruce Blumberg
Index����������������������������������������������������������������������������������������������������������������������������������������������615
Preface
Nutrition is the major environmental influence on metabolic systems that impact cardiovascular
health and disease. Past decades have seen major advances in the identification of specific dietary
effects on these systems. However, as this knowledge has grown, and the tools for studying these
effects have become more diverse and powerful, there has been growing appreciation of the com-
plexities and challenges facing those seeking to gain an in-depth yet comprehensive understanding
of dietary effects on cardiometabolic health. Intensifying this concern is the imperative of address-
ing the global increase in the incidence of cardiovascular disease, coupled with the diet-related
metabolic conditions—dyslipidemia, diabetes, and obesity—that play key roles in its pathogenesis.
In preparing this textbook, we have called on the expertise of scientists across a broad range of
topics and disciplines to assemble information aimed at researchers, clinicians, and other health
professionals who have interests in this important field.
The chapters in the first section of the textbook are clustered around the theme of energy balance
and adiposity as they relate to cardiometabolic health. An overview of the regulatory mechanisms
that determine energy balance is provided in Chapter 1 followed by a chapter on the critical role of
behavior in regulating eating (Chapter 2). The debate of whether “a calorie is a calorie” regardless
of food source is addressed in the next two chapters (Chapters 3 and 4), along with methods for
weight loss. Caloric restriction is addressed in Chapter 4 and bariatric surgery in Chapter 5. The
benefits of physical activity on cardiometabolic health, with or without weight loss, are addressed in
Chapter 6. The effects of diet on body fat distribution and the significance of the more metabolically
active central versus peripheral adiposity are the topics for Chapter 7. This section concludes with
Chapters 8 and 9 on nutritional considerations at different stages of the lifespan—in childhood and
adolescence, and in the elderly.
Sections II through IV of the book are devoted to evaluating macronutrient effects on cardio-
metabolic health. In Section II on dietary fats, the effects of polyunsaturated fatty acids, specifi-
cally omega-3 and omega-6 fatty acids, are discussed in Chapter 10. The role of dietary saturated
fats, along with the need to evaluate them in the context in which they are consumed, is reviewed
in Chapter 11. The effects of trans fatty acids on blood lipids and cardiovascular disease risk, with
consideration for industrially produced vs. ruminant trans fats, are discussed in Chapter 12, the third
and final chapter of this section.
In Section III, Chapters 13 and 14 on dietary carbohydrates and cardiometabolic health pay par-
ticular attention to the role of sugar—consumed in quantities 40 times what was consumed at the
time of the American Revolution in 1776. The quantity and quality of carbohydrates and the role of
carbohydrate restriction in improving metabolic health are reviewed in Chapters 15 and 16.
Section IV’s focus, dietary protein in relation to cardiometabolic health is covered in
Chapters 17 through 19, with a focus on its role in energy balance, skeletal muscle function, and
cardiovascular and diabetes risk.
A renewed interest and focus on whole foods and overall dietary patterns as a means toward
cardiovascular health has led to the development of unique and validated methods of analysis as
presented in Section V, Chapters 20 and 21. The two dietary patterns with the strongest evidence
base for cardioprotective effects, namely, the Mediterranean and DASH diets, are reviewed in
Chapters 22 and 23. Food groups that have been heavily touted and consumed include tree nuts
and dairy foods, and the evidence for effects of these food groups on cardiometabolic health are
reviewed in Chapters 24 and 25. The Section V concludes with Chapters 26 and 27 that present
more debated approaches toward cardiometabolic health, including Paleolithic diets and intermittent
fasting regimens.

ix
x Preface

In the last section of the textbook, Section VI, other nutritional factors impacting cardiometabolic
health are considered. Chapter 28 focuses on the role of nutrition in modulating gene expression
and epigenetics. Chapter 29 reviews gene–diet interactions that may contribute to interindividual
differences in dietary needs and responses. An assessment of the role of the intestinal microbiome
in modulating metabolic traits is provided in Chapter 30. Chapters 31 and 32, the final two chapters
discuss alcohol and endocrine disruptors as diet-related influences on cardiometabolic health.
We are grateful to the individuals who contributed well-researched and incisive chapters to this
textbook. It is our hope that the information assembled here will have value to those who share our
goal of applying nutritional science to reducing the burden of cardiovascular disease.
Editors
Nathalie Bergeron, PhD, is professor of biological sciences at
Touro University California College of Pharmacy and associ-
ate staff scientist in the Atherosclerosis Research Program at
Children’s Hospital Oakland Research Institute. She was trained
in dietetics and nutritional biochemistry and graduated from Laval
University, Canada, with a PhD in nutrition. She pursued her post-
doctoral training at the Cardiovascular Research Institute of the
University of California, San Francisco, where she specialized in
postprandial lipoprotein metabolism. Dr. Bergeron began her aca-
demic career as a research professor at Laval University in 1996.
She was a visiting professor in the Department of Nutritional
Sciences and Toxicology at the University of California, Berkeley, from 2000 to 2002 and joined the
Touro University, California College of Pharmacy, at its inception in 2005. At Touro, Dr. Bergeron
teaches in the areas of pathophysiology of metabolic diseases, as well as nutrition. She also holds a
staff scientist position at the Children’s Hospital Oakland Research Institute. Her research is clini-
cal in nature and focuses on dietary composition, with a special emphasis on carbohydrate quantity
and quality, and its relationship to features of atherogenic dyslipidemia. Her more recent research
activities include looking at variations of the DASH and Mediterranean dietary patterns and their
relationship to cardiometabolic health. Over the course of her academic career, she has received
research grants from the Medical Research Council of Canada, the Heart and Stroke Foundation
of Canada, the American Diabetes Association, and the National Institutes of Health, along with
investigator-initiated funding from the Dairy Farmers of Canada, the Dairy Research Institute, and
the Almond Board of California.

Patty W. Siri-Tarino, PhD, is an associate staff scientist in the

Atherosclerosis Research Program and program director of the
Family Heart & Nutrition Center at the Children’s Hospital Oakland
Research Institute. She earned her undergraduate degree in biol-
ogy at Tufts University, a Master of Science in epidemiology at the
Netherlands Institute of Health Sciences, and a PhD in nutrition and
metabolic biology at Columbia University, where she developed a
transgenic mouse model of insulin resistance, obesity, and dyslip-
idemia. Dr. Siri-Tarino began her postdoctoral work by developing
and conducting studies in humans aimed at understanding variabil-
ity in the postprandial response to high-fat meals and the role of
cholesterol absorption inhibitors in its modulation. She subsequently worked on dietary intervention
studies evaluating macronutrient effects on CVD risk profiles in the context of weight loss and sta-
bility as well as studies evaluating genetic effects on energy metabolism at rest and during exercise.
Dr. Siri-Tarino has spoken nationally and internationally on the role of diet on lipoprotein profiles
as biomarkers of cardiovascular disease and published peer-reviewed journal articles, reviews, book
chapters, and popular media articles on diet, lifestyle, and genetic determinants of heart health. She
is interested in community engagement and education.

xi
xii Editors

George A. Bray, MD, MACP, MACE, is a Boyd professor emeri-

tus at the Pennington Biomedical Research Center of Louisiana
State University in Baton Rouge, Louisiana, and professor of med-
icine emeritus at the Louisiana State University Medical Center
in New Orleans. After graduating from Brown University summa
cum laude in 1953, Dr. Bray entered Harvard Medical School,
graduating magna cum laude in 1957. His postdoctoral training
included an internship at the Johns Hopkins Hospital, Baltimore,
Maryland, a fellowship at the NIH, residence at the University of
Rochester, and fellowships at the National Institute for Medical
Research in London and at the Tufts-New England Medical Center
in Boston. In 1970, he became director of the Clinical Research Center at the Harbor UCLA Medical
Center and the organizer of the First Fogarty International Center Conference on Obesity in 1973.
Dr. Bray chaired the Second International Congress on Obesity in Washington, DC, in 1977. In
1989, he became the first executive director of the Pennington Biomedical Research Center in
Baton Rouge, a post he held until 1999. He is a Master of the American College of Physicians,
Master of the American College of Endocrinology, and Master of the American Board of Obesity
Medicine. Dr. Bray founded the North American Association for the Study of Obesity in 1982 (now
The Obesity Society), and he was the founding editor of its journal, Obesity Research, as well
as cofounder of the International Journal of Obesity and the first editor of Endocrine Practice,
the official journal of the American College of Endocrinologists. He has received many awards
during his medical career, including the Johns Hopkins Society of Scholars Award, Honorary
Fellow of the American Dietetic Association, the Bristol-Myers Squibb Mead-Johnson Award in
Nutrition, the Joseph Goldberger Award from the American Medical Association, the McCollum
Award from the American Society of Clinical Nutrition, the Osborne-Mendel Award from the
American Society of Nutrition, the TOPS Award, the Weight Watchers Award, the Stunkard
Lifetime Achievement Award, and the Presidential Medal from The Obesity Society. During his
50 academic years, he authored or coauthored more than 1900 publications, ranging from peer-
reviewed articles and reviews to books, book chapters, and abstracts reflected in his Hirsch (H)
Index of 89. Dr. Bray has had a long interest in the history of medicine and has written articles
and a book on the ­history of obesity.

Ronald M. Krauss, MD, is senior scientist and Dorothy Jordan

Endowed Chair at Children’s Hospital Oakland Research Institute,
professor of medicine at UCSF, and adjunct professor of nutri-
tional sciences at UC Berkeley. He earned his undergraduate and
medical degrees from Harvard University with honors and served
his internship and residency in the Harvard Medical Service of
Boston City Hospital. He then joined the staff of the National
Heart, Lung, and Blood Institute in Bethesda, Maryland, first as
clinical associate and then as senior investigator in the Molecular
Disease Branch. Dr. Krauss is board certified in internal medicine,
endocrinology, and metabolism, and is a member of the American
Society for Clinical Investigation, a fellow of the American Society of Nutrition and the American
Heart Association (AHA), and a distinguished fellow of the International Atherosclerosis Society.
He has served on the U.S. National Cholesterol Education Program Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults; was the founding chair of the
AHA Council on Nutrition, Physical Activity, and Metabolism; and is a national spokesperson
for the AHA. He has also served on both the Committee on Dietary Recommended Intakes for
Macronutrients and the Committee on Biomarkers of Chronic Disease of the Institute of Medicine of
the National Academy of Sciences. He has received numerous awards, including the AHA Scientific
Editors xiii

Councils Distinguished Achievement Award, the Centrum Center for Nutrition Science Award
of the American Society for Nutrition, the Distinguished Leader in Insulin Resistance from the
International Committee for Insulin Resistance, and the AHA Award of Meritorious Achievement.
In addition, he has been the Robert I. Levy Lecturer of the AHA, the Edwin Bierman Lecturer for
the American Diabetes Association, and the Margaret Albrink Lecturer at West Virginia University
School of Medicine. Dr. Krauss is on the editorial boards of a number of journals and has been
associate editor of Obesity, the Journal of Lipid Research, and the Journal of Clinical Lipidology.
He has published nearly 500 research articles and reviews on genetic, dietary, and drug effects on
plasma lipoproteins and coronary artery disease. Among his accomplishments is the identification
of atherogenic dyslipidemia, a prevalent lipoprotein trait (high triglyceride, low HDL, and increase
in small, dense LDL particles) that is associated with risk of cardiovascular disease and type 2
­diabetes. In recent years, his work has focused on interactions of genes with dietary and drug treat-
ments that affect metabolic phenotypes and cardiovascular disease risk.
Contributors
Brian J. Bennett Julie Brothers
Western Human Nutrition Research Center Division of Cardiology
Agricultural Research Service The Children’s Hospital of Philadelphia
United States Department of Agriculture Philadelphia, Pennsylvania
Davis, California
Pedro Carrera-Bastos
Silvia Berciano Center for Primary Health Care Research
Faculty of Pharmacy Lund University
Universidad Autonoma de Madrid, Spain Lund, Sweden
Madrid, Spain
Elizabeth M. Cespedes Feliciano
and
Kaiser Permanente Northern California
Jean Mayer USDA Human Nutrition Research Oakland, California
Center on Aging
Tufts University Raquel Chamorro-Garcia
Boston, Massachusetts Department of Developmental and
Cell Biology
Nathalie Bergeron University of California, Irvine
College of Pharmacy Irvine, California
Touro University California
Vallejo, California Catherine M. Champagne
Pennington Biomedical Research Center
and Baton Rouge, Louisiana
Children’s Hospital Oakland Research Institute
Oakland, California Peter Clifton
Alliance for Research in Exercise, Nutrition
and Activity (ARENA)
Bruce Blumberg
Sansom Institute for Health Science
Department of Developmental and Cell Biology
School of Pharmacy and Medical Sciences
and
University of South Australia
Department of Pharmaceutical Sciences
Adelaide, South Australia, Australia
University of California, Irvine
Irvine, California
Stephen R. Daniels
Department of Pediatrics
George A. Bray University of Colorado School of Medicine
Pennington Biomedical Research Center Aurora, Colorado
Baton Rouge, Louisiana
and Michel de Lorgeril
Laboratoire Cœur et Nutrition
Children’s Hospital Oakland Research Institute Faculté de Médecine
Oakland, California Grenoble, France

Andrea M. Brennan Lynda Frassetto

School of Kinesiology and Health Studies School of Medicine
Queen’s University University of California, San Francisco
Kingston, Ontario, Canada San Francisco, California

xv
xvi Contributors

Clint Gray Karim Kheniser

Liggins Institute and Gravida: National Centre Department of Endocrinology, Diabetes
for Growth and Development and Metabolism
University of Auckland Cleveland Clinic
Auckland, New Zealand Cleveland, Ohio
Kevin D. Hall
National Institute of Diabetes and Digestive and Ronald M. Krauss
Kidney Diseases Children’s Hospital Oakland Research
National Institutes of Health Institute
Bethesda, Maryland Oakland, California

William S. Harris
Penny Kris-Etherton
Department of Internal Medicine
Department of Nutritional Sciences
Sanford School of Medicine
The Pennsylvania State University
University of South Dakota
University Park, Pennsylvania
and
OmegaQuant Analytics, LLC
Sioux Falls, South Dakota Sofia Laforest
School of Nutrition
Peter J. Havel Laval University
Department of Molecular Biosciences and
School of Veterinary Medicine Quebec Heart and Lung Institute
and Québec City, Québec, Canada
Department of Nutrition
University of California, Davis
Benoît Lamarche
Davis, California
Institute of Nutrition and Functional Foods
Frederick M. Hecht School of Nutrition
Department of Medicine Laval University
University of California, San Francisco Québec City, Québec, Canada
San Francisco, California
Charlotte Holst Donald K. Layman
National Institute of Public Health Department of Food Science and Human
University of Southern Denmark Nutrition
Copenhagen, Denmark University of Illinois at Urbana-Champaign
Urbana, Illinois
Frank B. Hu
Department of Nutrition
Staffan Lindeberg
and
Center for Primary Health Care Research
Department of Epidemiology
Lund University
Harvard University School of Public Health
Lund, Sweden
Boston, Massachusetts
Grace Marie Jones Christina Link
College of Medicine Department of Nutritional Sciences
Touro University California The Pennsylvania State University
Vallejo, California University Park, Pennsylvania
Sangeeta Kashyap
Department of Endocrinology, Diabetes Caitlin Lynch
and Metabolism Department of Nutritional Sciences
Cleveland Clinic The Pennsylvania State University
Cleveland, Ohio State College, Pennsylvania
Contributors xvii

Geneviève B. Marchand Jose M. Ordovas

School of Nutrition IMDEA Alimentación
Laval University and
and Centro Nacional de Investigaciones
Quebec Heart and Lung Institute Cardiovasculares
Québec City, Québec, Canada Madrid, Spain
and
Eveline A. Martens
Dutch Kidney Foundation Jean Mayer USDA Human Nutrition Research
Bussum, the Netherlands Center on Aging
Tufts University
Ashley E. Mason Boston, Massachusetts
UCSF Department of Psychiatry
UCSF Osher Center for Integrative Medicine Jennifer Panganiban
San Francisco, California Division of Gastroenterology, Hepatology, and
Nutrition
The Children’s Hospital of Philadelphia
Richard D. Mattes
Philadelphia, Pennsylvania
Department of Nutrition Science
College of Health and Human Sciences Elizabeth Prout Parks
Purdue University The Children’s Hospital of Philadelphia
West Lafayette, Indiana and
Perelman School of Medicine
Ronald P. Mensink The University of Pennsylvania
Department of Human Biology Philadelphia, Pennsylvania
NUTRIM School of Nutrition and Translational
Research in Metabolism Surya Panicker Rajeev
Maastricht University Medical Center Institute of Ageing and Chronic Disease
Maastricht, the Netherlands University of Liverpool
and
Aintree University Hospital NHS Foundation
Katie A. Meyer
Trust
Department of Nutrition
Liverpool, United Kingdom
Nutrition Research Institute
University of North Carolina at Chapel Hill Leanne M. Redman
Chapel Hill, North Carolina Division of Clinical Sciences
Pennington Biomedical Research Center
Jasper Most Baton Rouge, Louisiana
Division of Clinical Sciences
Pennington Biomedical Research Center Clare M. Reynolds
Baton Rouge, Louisiana Liggins Institute and Gravida: National Centre
for Growth and Development
University of Auckland
Kathleen Mulligan
Auckland, New Zealand
College of Medicine
Touro University California Robert Ross
Vallejo, California School of Kinesiology and Health Studies
and
and
Division of Endocrinology and Metabolism
Department of Medicine Department of Medicine
University of California, San Francisco Queen’s University
San Francisco, California Kingston, Ontario, Canada
xviii Contributors

Jordi Salas-Salvadó Janne Schurmann Tolstrup

Hospital Universitari de Sant Joan de Reus National Institute of Public Health
Universitat Rovira i Virgili University of Southern Denmark
Reus, Spain Copenhagen, Denmark
Jean-Marc Schwarz
College of Medicine John F. Trepanowski
Touro University California Department of Kinesiology and Nutrition
Vallejo, California University of Illinois, Chicago
Chicago, Illinois
and
Krista A. Varady
Department of Medicine Department of Kinesiology and Nutrition
University of California, San Francisco University of Illinois, Chicago
San Francisco, California Chicago, Illinois
Ian W. Seetho Mark H. Vickers
Institute of Ageing and Chronic Disease Liggins Institute and Gravida: National Centre
University of Liverpool for Growth and Development
and University of Auckland
Aintree University Hospital NHS Foundation Auckland, New Zealand
Trust
Liverpool, United kingdom Maelán Fontes Villalba
Center for Primary Health Care Research
Patty W. Siri-Tarino Lund University
Children’s Hospital of Oakland Research Lund, Sweden
Institute
Oakland, California Margriet S. Westerterp-Plantenga
Department of Human Biology
Kimber L. Stanhope School of Nutrition and Translational Research
Department of Molecular Biosciences in Metabolism
School of Veterinary Medicine Maastricht University
and Maastricht, the Netherlands
Department of Nutrition
University of California, Davis John P.H. Wilding
Davis, California Institute of Ageing and Chronic Disease
University of Liverpool
André Tchernof and
School of Nutrition Aintree University Hospital NHS Foundation
Laval University Trust
and Liverpool, United Kingdom
Quebec Heart and Lung Institute
Québec City, Québec, Canada Edward Yu
Department of Nutrition
Alyssa Tindall and
Department of Nutritional Sciences Department of Epidemiology
The Pennsylvania State University Harvard University School of Public Health
University Park, Pennsylvania Boston, Massachusetts
Section I
Energy Balance, Adiposity, and
Cardiometabolic Health
 1 The Gut–Brain Axis
Regulation of Food Intake

Surya Panicker Rajeev, Ian W. Seetho, and John P.H. Wilding

CONTENTS
Introduction.........................................................................................................................................4
Central Nervous System Regulation of Food Intake...........................................................................4
Brainstem Regulation.....................................................................................................................4
Hypothalamus................................................................................................................................6
Arcuate Nucleus........................................................................................................................6
Paraventricular Nucleus.............................................................................................................6
Lateral Hypothalamus...............................................................................................................6
Dorsal Medial Nucleus and Ventromedial Nucleus of the Hypothalamus................................6
Neurotransmitters and Homeostatic Control of Food Intake.........................................................7
Neuropeptide Y and Agouti-Related Peptide............................................................................7
Proopiomelanocortin and Cocaine- and Amphetamine-Regulated Transcript..........................7
Gastrointestinal Signals That Regulate Food Intake...........................................................................8
Gut Hormones..............................................................................................................................10
Ghrelin ....................................................................................................................................10
Cholecystokinin.......................................................................................................................11
Pancreatic Polypeptide............................................................................................................11
Glucagon-Like Peptide-1 and Peptide YY..............................................................................12
Glucagon-Like Peptide-1........................................................................................................12
Peptide YY..............................................................................................................................13
Oxyntomodulin........................................................................................................................14
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Amylin ....................................................................................................................................15
Mechanical Mechanisms..............................................................................................................15
The Ileal-Brake Reflex............................................................................................................15
The Role of Mechanoreception in Appetite Control...............................................................15
Effect of Bariatric Surgery on Gut Hormones.........................................................................15
Diet and the Gut–Brain Axis: Are All Macronutrients Equal?................................................16
Conclusion........................................................................................................................................17
References.........................................................................................................................................17

ABSTRACT
Regulation of food intake is a fundamental biological homeostatic process and is regulated at multiple
levels. The process begins with sight, smell, and taste of food, the act of ingestion evoking either plea-
surable or unpleasant sensations via these routes, which can themselves enhance, decrease, or even stop
intake. Once food enters the gastrointestinal tract, it evokes a cascade of responses to its mechanical
and chemical properties that have the function of coordinating orderly digestion, ensuring an appropri-
ate metabolic fate for nutrients, and activating the process of satiation that ultimately leads to the end
of the meal. This process of satiation involves signaling to the brain via neural, humoral, and hormonal
signals from the gut. Brain signals are primarily detected in the brainstem and hypothalamus, which

3
4 Nutrition and Cardiometabolic Health

contain networks of neurons that are able to respond both to these messages and to important long-term
signals of energy stores, most importantly the fat-derived hormone, leptin. These biological processes
are also sensitive to and modulated by higher brain centers that are sensitive to hedonic signals, social
context, and mood. Ultimately body weight is regulated by the net balance between intake and energy
expenditure, the latter also being modifiable by many of the same neurotransmitter signals that influence
food intake. The system seems biased toward weight gain, as a negative energy balance evokes a strong
corrective response with a drive to increase intake and reduce expenditure; in contrast, the response
to excess is weak and may be more easily overridden by hedonic and other higher centers. This may
explain the difficulty many people have in maintaining a healthy weight.

INTRODUCTION
The mechanism of energy homeostasis is complex and influenced by various factors including nutri-
ent availability and loss, hormone levels, genetic factors, and environmental stimuli. The system is
also set in such a way to be more responsive to energy loss than gain [1], which poses a challenge
in combating the obesity pandemic. The fundamental control of intake of energy/food starts with
the sight, smell, and taste of food, the process of digestion in the gut, and finishes in the brain with
physiological interactions at multiple levels.
The “gut–brain axis” describes the channels of communication between the gastrointestinal tract
and the appetite control areas of the central nervous system (CNS). The gut responds to nutrients and
mechanical stretch by generation of neural and hormonal signals to the brain with its homeostatic
and hedonic regions. Apart from the gut and brain, adipose tissue and its hormones, notably leptin,
play a major role in the regulation of appetite control and energy homeostasis.
The brain, through its hypothalamic nuclei as well as brainstem connections, plays an important part
in regulating energy homeostatic mechanisms and hence is a potential target for drug therapy, although
“off target” effects may limit this approach. The hypothalamus has orexigenic and anorexigenic neurons
and can sense nutrient changes and alterations in the hormonal milieu including gut hormones. There
are homeostatic and non-homeostatic systems involved in appetite control. While the former operate
through the hypothalamus, brainstem, and gut, the non-homeostatic (environmental and hedonic) mech-
anisms influence food intake via the corticolimbic system.
The gastrointestinal (GI) system secretes various endocrine hormones and apart from exerting effects
on several aspects of GI function, the gut sends neural and humoral signals to various brain regions,
which are initially processed in the hypothalamus and brainstem. The gut–brain axis is the two-way
interaction between the gut (through neural, nutrient, and hormonal factors) and the CNS (mainly in the
hypothalamus and brainstem) and plays an important role in the maintenance of energy homeostasis by
the human body. Short-term signals including gut hormones and neural pathways (vagal and spinal vis-
ceral afferents) moderate meal intake and satiation. Long-term humoral signals involved in the regulation
of energy homeostasis include leptin, the adipose tissue hormone, and insulin, the pancreatic hormone.

CENTRAL NERVOUS SYSTEM REGULATION OF FOOD INTAKE

In this part of the chapter, we review the literature describing the role of the CNS in the control of
food intake and show how this integrates peripheral signals from the gut and elsewhere to regulate
energy homeostasis (Figure 1.1).

Brainstem Regulation
The CNS mediates energy balance in the body and is a key regulator of energy homeostasis. The
brain receives signals from the gastrointestinal tract via both the nervous system and the circulation.
Vagal afferents from the gut converge at the brainstem dorsal vagal complex (DVC), composed of
the dorsal motor nucleus of the vagus, the area postrema, and nucleus of the tractus solitarius (NTS).
Regulation of Food Intake 5

PVN

DMH PFA

VMH LHA
Third ventricle

ARC (NPY/AgRP and

POMC/CART) Brain stem
(NTS, AP, DVC)
Median eminence

Adipose tissue Leptin

Vagus
Insulin
Pancreas Pancreatic
Polypeptide

Stomach Ghrelin

CCK
GLP-1
Intestine PYY
OXM

FIGURE 1.1 Links between the peripheral signals and central regulation of feeding. Numerous neural path-
ways transmit sensory information from the upper gastrointestinal viscera. Inputs are relayed to the NTS, AP,
and DVC; signals from mechanical and chemical stimuli from the stomach and intestine initially via vagal
afferents. Signals are relayed to the hypothalamus and appetite-regulating areas of the brain. ARC, arcuate
nucleus; AgRP, agouti-related peptide; AP, area postrema; CART, cocaine- and amphetamine-regulated tran-
script; CCK, cholecystokinin; DMH, dorsomedial nucleus of hypothalamus; DVC, dorsal vagal complex;
GLP-1, glucagon-like peptide 1; LHA, lateral hypothalamic area; NPY, neuropeptide Y; NTS, nucleus of trac-
tus solitarius; OXM, oxyntomodulin; POMC, proopiomelanocortin; PP, pancreatic polypeptide; PVN, paraven-
tricular nucleus; PYY, peptide YY; PFA, perifornical area; VMH, ventromedial hypothalamus.

The NTS is in close proximity to the area postrema with an incomplete blood–brain barrier and also
responds to peripheral signals in the circulation as well as vagal afferents from the gastrointestinal
tract [2]. The DVC subsequently projects to the hypothalamus and higher brain centers [3]. Leptin,
insulin, and glucose-sensing receptors are expressed in the brainstem [3,4].
The NTS in the medulla receives afferent gustatory signals via vagal nerve stimulation (e.g.,
from mechanoreceptors detecting gastric distension and chemoreceptors detecting changes in
nutrient composition and pH). The vagus also facilitates transmission of gut hormone signals
such as cholecystokinin (CCK), ghrelin, pancreatic polypeptide (PP), and glucagon-like peptide-1
6 Nutrition and Cardiometabolic Health

(GLP-1) that are regulated by the presence of food in the gastrointestinal tract [3,5]. The NTS and
parabrachial nucleus in the brainstem innervate the hypothalamic paraventricular nuclei, arcuate
nuclei, and dorsomedial nucleus of hypothalamus (DMH), as well as the lateral hypothalamic area
(LHA), central nucleus of the amygdala, and nucleus of the stria terminalis. The visceral sensory
cortex integrates taste sensation and communicates with the thalamus, which has projections from
the NTS to mediate perceptions of fullness and satiety.

Hypothalamus
Arcuate Nucleus
Within the hypothalamus, the arcuate nucleus (ARC) at the base of the median eminence in the
floor of the third ventricle integrates neural and hormonal signals regulating peripheral satiety and
adiposity through neuropeptide orexigenic and anorexigenic transmission to other brain regions.
These include orexigenic neuropeptides such as neuropeptide Y (NPY) and Agouti-related peptide
(AgRP) and anorexigenic neuropeptides such as proopiomelanocortin (POMC) and cocaine- and
amphetamine-regulated transcript (CART). Peripheral signals influence the activity of these neuro-
nal populations to change feeding behavior and energy homeostasis [6].
The ARC is composed of neuronal cell bodies that express receptors for peripheral signals such as
gut hormones and adipokines and is accessible to circulating peripheral factors across the incomplete
blood–brain barrier and by carrier-mediated transport. ARC neuronal populations are linked with
second-order neurons in other hypothalamic nuclei that include the paraventricular nucleus (PVN),
LHA, DMH, and ventromedial hypothalamus (VMH). From these nuclei, the second-order neurons
project onto the caudal brainstem, cortex, and limbic system.
Paraventricular Nucleus
NPY/AgRP and POMC/CART neurons in the ARC send projections to the PVN of the hypothala-
mus. The PVN is adjacent to the superior part of the third ventricle in the anterior hypothalamus
and the neurons express anorexigenic peptides corticotrophin-releasing hormone (CRH) and thy-
rotropin-releasing hormone (TRH). The PVN integrates the thyroid and hypothalamic–pituitary–
adrenal axes with nutritional signals, thus allowing for responsiveness to alterations in metabolic
rate and sympathetic activity [7,8]. NPY/AgRP downregulates CRH and TRH while α-melanocyte-
stimulating hormone (α-MSH) increases CRH and TRH expression.
The PVN also contains synaptic terminals for NPY, α-MSH, serotonin (5-HT), noradrenaline, and
opioid peptides and appetite-regulating signals such as ghrelin, orexin A, CCK, and leptin, which can alter
food intake and body weight [9]. The PVN may have an inhibitory role in food intake as hyperphagia is
produced by central administration of NPY into the PVN and by destruction of the PVN [10]. The PVN
has projections to the midbrain, prelocus coeruleus in dorsal pons, and NTS in the ventral medulla [3].
Lateral Hypothalamus
The LHA comprises populations of nuclei that receive projections from the ARC and express the orexi-
genic neuropeptides melanin-concentrating hormone (MCH) and orexin [3]. NPY neurons synapse with
orexin and MCH nuclei in the LHA. MCH levels rise during fasting and stimulate appetite [11]. Excess
MCH expression in transgenic mice leads to obesity [12], while mice with MCH deficiency are lean [13].
Orexins A and B stimulate appetite and are produced by neurons in the LHA that project to the olfactory
bulb, cerebral cortex, thalamus, hypothalamus, brainstem, locus coeruleus, tuberomammillary nucleus,
and raphe nucleus [2]. Glucose-sensing neurons have been found in the LHA, ARC, and ventromedial
nucleus of hypothalamus that respond to fluctuations in local extracellular glucose concentration [3,4].
Dorsal Medial Nucleus and Ventromedial Nucleus of the Hypothalamus
The DMH is dorsal to the VMH and receives neuronal NPY/AgRP projections from the ARC and
projects α-MSH to the PVN [3]. α-MSH activates catabolic pathways to reduce food intake and
enhance energy expenditure.
Regulation of Food Intake 7

LHA and perifornical area

PVN
MC4 receptor
Increase NPY Y5 CART Decrease
food intake receptors receptor food intake
+ – +

Arcuate POMC (α-MSH)

NPY AGRP nucleus CART
+ Neurotensin
+
+ –
– –

Ghrelin PYY3–36 GLP–1 Leptin

GI tract (gut hormones) Adipose tissue

FIGURE 1.2 Schematic of the hypothalamic nuclei and interactions with peripheral signals. LHA, lateral
hypothalamic area; PVN, paraventricular nucleus; NPY, neuropeptide Y; AGRP, agouti-related protein; POMC,
pro-opiomelanocortin; CART, cocaine and amphetamine-related transcript; α-MSH, α-melanocyte-stimulating
hormone; MC4, melanocortin 4.

The VMH has connections with the PVN, DMH, and the LHA. In the VMH, brain-derived neu-
rotrophic factor is expressed and acts to suppress food intake through MC4 receptor activation.
Hyperphagia and obesity have been found in mice with selective loss of brain-derived neurotrophic
factor pathways in the VMH and DMH [3] (Figure 1.2).

Neurotransmitters and Homeostatic Control of Food Intake

Neuropeptide Y and Agouti-Related Peptide
The ARC contains NPY and AgRP neuronal populations that express receptors for circulating satiety
signals. Neuronal activation leads to positive energy balance, lower energy expenditure, and increased
food intake. NPY is a neuropeptide that has orexigenic effects mediated by G-protein-coupled recep-
tors (hypothalamic Y1 and Y5 receptors) and levels are associated with nutritional status, with levels
being increased during fasting and reduced following food intake [14]. Studies have shown that the
administration of NPY in the CNS of rats stimulates food intake and increases body weight [15].
The AgRP is expressed in the ARC and is secreted with NPY. AgRP is an antagonist of melanocortin
receptors in the melanocortin system (MC3 and MC4 receptors) and stimulates appetite. Increased
expression occurs in periods of fasting and acts to increase food intake [16].

Proopiomelanocortin and Cocaine- and Amphetamine-Regulated Transcript

The POMC and CART neuronal populations respond to satiety and their activation promotes negative
energy balance, increased energy expenditure, and decreased food consumption. POMC is a precursor
polypeptide of melanocortins such as the α-MSH that act at MC3 and MC4 receptors to control appetite.
Nutritional status regulates mRNA POMC expression and this is decreased during fasting periods and
conversely increased with feeding. Administration of agonists for MC3 and MC4 receptors reduces
food intake and of antagonists at the receptors produces hyperphagia [10]. α-MSH acts as the agonist at
the hypothalamic MC3 and MC4 receptors to suppress appetite [3]. In murine models of POMC defi-
ciency, obesity and decreased metabolic rate occur and these effects are reversed by administration of
melanocortins that suppress food intake. In humans, perturbations such as congenital POMC deficiency
and MC3 and MC4 receptor mutations have been associated with obesity [17].
CART has anorexigenic properties and regulates energy homeostasis as neuronal expression
responds to nutritional status. It modulates the actions of NPY and leptin. Administration of CART
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