The effect of macronutrient composition on energy expenditure and fat balance – is it true that a calorie is a calorie?
Current research and public health policy on obesity is largely based on the hypothesis that the fundamental cause of the condition is an energy imbalance between calories consumed and expended. By this hypothesis, the interaction between diet and body fat is determined by the caloric content of the foods consumed, while the macronutrient content of the diet (the proportion and type of carbohydrates, fats, and protein) has no meaningful effect. This is often summed up by the assertion that “a calorie-is-a-calorie,” shorthand for the hypothesis that a calorie’s worth of protein has an equivalent effect on the accumulation and storage of fat in the human body (on “adiposity”) as does a calorie of carbohydrate or a calorie of fat. An alternative hypothesis is that the macronutrient composition of the diet influences adiposity through its effect on the hormones that regulate uptake of fat (technically “fatty acids”) by fat cells and their subsequent mobilization and use for fuel (that is, oxidation).
This study is one of two studies currently funded by Nutrition Science Initiative (NuSI) that are designed to test this “calorie-is-a-calorie” hypothesis – in this case, in the context of fixed energy intake under maximum control on human subjects. While studies dating back to the 1930s have attempted to investigate the relationship between dietary macronutrient composition and body fat under controlled conditions, these studies were typically based on untested assumptions and lacked either the rigor or power to provide meaningful results.
The pilot study was designed to utilize the most rigorous environmental and dietary controls to isolate the effect of dietary carbohydrate and fat on metabolism. This study confined participants in a metabolic ward and carefully determined their caloric requirements while they maintain a constant body composition on a standard American diet (50 % carbohydrate, 35% fat and 15% protein). After four weeks of this diet, the participants were shifted to a diet of identical caloric content, but radically different macronutrient composition. In this diet, known as a “ketogenic” diet, the carbohydrate content is reduced to only 5 % of calories; fat content is increased to 80% (protein content remains unchanged). By keeping calories constant while making this radical shift in carbohydrate and fat content, the study constituted a robust test of the hypothesis that the interaction between diet and body fat is determined by the caloric content of the diet independent of macronutrient composition.
This pilot study provided a trial run of the methodologies that in turn will be used in a larger, randomized controlled trial of longer duration that will constitute an even more rigorous test of the hypothesis. The results will also provide the necessary data to “power” the follow-up study – that is, to determine how many participants will be necessary for a reliable test of the hypothesis. Because the pilot study may be too short in duration to detect a significant change in fat mass under these conditions, the primary outcome measure of the study is the change in total energy expenditure of the participants during the four weeks on the ketogenic diet. If the restriction of carbohydrates in the ketogenic diet reduces fat mass, the crossover to the ketogenic diet will be accompanied by an increase in energy expenditure.
This study will provide insight into whether the macronutrient composition of the diet – specifically fat and carbohydrate – influences adiposity and energy expenditure, independent of total calories consumed.
New York, New York, 10027
National Institutes of Health, NIDDK
Bethesda, Maryland, 20800
Pennington Biomedical Research Center
Baton Rouge, Louisiana, 70808
Translational Research Institute
Orlando, Florida, 32804
University of California, San Francisco
500 Parnassus Ave
San Francisco, CA 94143
Rudolph Leibel, M.D.
Michael Rosenbaum, M.D.
Laurel Mayer, M.D.
B. Timothy Walsh, M.D.
National Institutes of Health, NIDDK
Kevin Hall, Ph.D. (Co-principal investigator)
Marc Reitman, M.D., Ph.D.
Kong Y. Chen, Ph.D.
Pennington Biomedical Research Center
Eric Ravussin, Ph.D. (Co-principal investigator)
Translational Research Institute for Metabolism and Diabetes
Steven R. Smith, M.D.
University of California, San Francisco
Peter J. Turnbaugh, Ph.D.
Current research and public health policy on obesity is based on the belief that it is caused by an imbalance between energy consumed (the calories we eat) and expended (the calories we excrete and burn). By this thinking, the interaction between diet and body fat is determined by the total amount of calories in the foods consumed, while the macronutrient content of these foods (the proportion and type of carbohydrates, fats, and protein) has no meaningful effect. In short, when it comes to fat accumulation, a “calorie-is-a-calorie,” regardless of its source. An alternative hypothesis is that dietary macronutrients influence body fat through their effect on the hormones that regulate the uptake, retention and mobilization of fat by fat cells, and the use of fat by other cells for fuel. This study will be the well-controlled test of these competing hypotheses to date.
The first step in the research program was conducting a pilot study to address scientific, statistical, technical, and logistics issues in the first multi-site study of its kind. Overweight and obese subjects lived in a clinical residence under tightly controlled conditions for eight weeks. For the first four weeks they were fed a typical American diet at precisely the amount of calories necessary for them to maintain a stable body composition. For the next four weeks, they were fed an equivalent amount of calories of a diet that replaces virtually all of the carbohydrate in the diet with fat. The “calorie-is-a-calorie” hypothesis predicts that the subjects would maintain a constant amount of body fat despite this radical change in the macronutrient composition of their diets, and so would expend an equivalent amount of energy on both diets. The alternative hypothesis predicts that the subjects would mobilize fat from their fat cells on the very-low-carbohydrate diet and burn that fat for fuel over and above the calories they were consuming. As a result, they would expend more energy during the second four-week period than the first. Among the objectives of this preliminary study the most critical is to determine whether in a study conducted at four different locations, the techniques and equipment provided the sensitivity required to reliably detect the relatively small changes in energy expenditure. This pilot study therefore sets the stage for a fully designed experiment that will have fundamental implications for how obesity is understood, treated and, ultimately, prevented.
Rudolph Leibel is the Christopher J. Murphy Professor of Diabetes Research, a Professor of Pediatrics and Medicine, and Head of the Division of Molecular Genetics in the Department of Pediatrics at Columbia University. He is also Co-Director of the Naomi Berrie Diabetes Center, the New York Obesity Research Center, and the Columbia University Diabetes and Endocrinology Research Center. His research focuses on studies of adipose tissue biochemistry and cellular physiology, the molecular genetics of body weight control and of type 2 diabetes. Dr. Leibel has served as an Associate Editor of the Journal of Clinical Investigation.
Michael Rosenbaum is a Professor of Clinical Pediatrics and Medicine and Associate Program Director of the CTSA and Clinical Research Resource at Columbia University Medical Center. Dr. Rosenbaum received his M.D. from Cornell University Medical College. Dr. Rosenbaum studies the metabolic, endocrine, and nervous system functions that make weight loss maintenance difficult, and has developed a unique inpatient study design that requires collaboration of individuals at multiple institutions.
Laurel Mayer is an Associate Professor of Clinical Psychiatry at Columbia University Medical Center and the Clinical Director of the Eating Disorders Research Unit at the New York State Psychiatric Institute. She received her M.D. from the Albert Einstein College of Medicine. Dr. Mayer’s interests include neuroendocrine, body composition and metabolic changes that occur in anorexia nervosa, and her current research focuses on the study of eating behavior and eating-related cognitions across the weight spectrum, extending her work from anorexia nervosa into obesity.
B. Timothy Walsh is the Ruane Professor of Pediatric Psychopharmacology at the College of Physicians & Surgeons, Columbia University, and the Director of the Division of Clinical Therapeutics at New York State Psychiatric Institute. His research examines the biological and psychological abnormalities that contribute to disturbances in eating behavior, and psychological and pharmacological treatments for anorexia nervosa, bulimia nervosa, and binge eating disorder. Dr. Walsh chaired the Eating Disorders Workgroup for DSM-5. He is a past president of the Academy for Eating Disorders, and of the Eating Disorders Research Society.
Kevin Hall is a Senior Investigator at the National Institute of Diabetes and Digestive and Kidney Diseases, one of the National Institutes of Health (NIH), where he studies macronutrient metabolism and body weight regulation. Dr. Hall received his Ph.D. in biophysics at McGill University in 1999. His laboratory at the NIH performs experiments in both humans and rodents and develops mathematical models and computer simulations to help design, predict, and interpret the experimental data.
Marc Reitman is a Senior Investigator and Chief of the Diabetes, Endocrinology, and Obesity branch at the National Institute of Diabetes and Digestive and Kidney Diseases, one of the National Institutes of Health. His research involves increasing mechanistic knowledge of energy homeostasis in order to better understand and treat diabetes and obesity. Dr. Reitman received his M.D. and Ph.D. from Washington University in St. Louis in 1983. Dr. Reitman currently serves as an Associate Editor of Obesity and serves on the American Diabetes Association Research Grant Review Panel.
Kong Chen is Director of the Metabolic Research Core at the National Institute of Diabetes and Digestive and Kidney Diseases, where he studies human energy expenditure, physical fitness, and body composition. Dr. Chen received his Ph.D. in biomedical engineering and his M.S. in clinical investigation from Vanderbilt University. His laboratory at NIH currently studies the capacity and the mechanism of non-shivering thermogenesis and brown adipose tissue.
Eric Ravussin is a Boyd Professor at Louisiana State University, the Douglas L. Gordon Chair in Diabetes and Metabolism, and the Chief of the Division of Health and Performance Enhancement at Pennington Biomedical Research Center. His previous lab at NIH was first in the world that allowed complete measurement of energy expenditure. Dr. Ravussin is the 2010 recipient of the Willendorf Award from the International Association for the Study of Obesity, the 2011 George Bray Founders Award for his contributions to the field of obesity, and serves as the Editor in Chief of Obesity.
Steven R. Smith is the Scientific Director of the Translational Research Institute for Metabolism and Diabetes in Orlando, Florida. He studies obesity, diabetes, and the metabolic origins of cardiovascular disease. Dr. Smith received his M.D. from the University of Texas Health Science Center in 1988. Dr. Smith has a special interest in the identification and development of drugs for the treatment of obesity and diabetes. He also serves as President-elect of The Obesity Society, a nonprofit organization seeking to educate patients and physicians, reform policy, and research obesity.
Peter J. Turnbaugh is an Assistant Professor in the Department of Microbiology and Immunology at the University of California, San Francisco, where he studies the metabolic activities and effects of gut microbes, including the impact of the gut microbiome on nutrition and drug metabolism. Dr. Turnbaugh received his Ph.D. in microbial genomics from Washington University in St. Louis in 2009.
David B. Allison is a Distinguished Professor, Quetelet Endowed Professor of Public Health, Associate Dean for Science, and Director of the Office of Energetics and the Nutrition Obesity Research Center at University of Alabama at Birmingham. His interests include obesity, quantitative genetics, clinical trials, and statistical and research methodology. Dr. Allison was awarded the 2006 Presidential Award for Excellence in Science, Mathematics, and Engineering Mentoring, and in 2012 was elected to the Institute of Medicine. He is the founding Field Chief Editor of Frontiers in Genetics and serves as an Associate Editor of Obesity.
John E. Blundell holds the Research Chair of PsychoBiology and is the founder Director of the Institute of Psychological Sciences, Faculty of Medicine and Health, at the University of Leeds, United Kingdom. He is one of the most highly cited investigators in the science of appetite regulation, energy balance and physical activity with over 20 years’ experience in the management of interdisciplinary interventions involving simultaneous measurements in metabolism, physiology, energy balance, behavior and psychology.
David D’ Alessio is a Professor of Medicine at Duke University School of Medicine, Director of the Division of Endocrinology, and a staff physician at the Durham VA Medical Center. Dr. D’Alessio has a primary research interest in the regulation of glucose tolerance and abnormalities that lead to type 2 diabetes. Work in his lab is directed at the interplay between circulating glucose, GI hormones, and neural signals to control insulin secretion.
Marc Hellerstein is a Professor of Medicine and occupies the Dr. Robert C. and Veronica Atkins Chair in Metabolic Nutrition at the University of California, Berkeley and maintains a joint appointment in the Department of Medicine at the University of California, San Francisco. Dr. Hellerstein completed medical training at Yale Medical School with a fellowship in endocrinology at New England Medical Center and a Ph.D. in nutritional biochemistry from Massachusetts Institute of Technology. Dr. Hellerstein’s major research interest has been the measurement in vivo of metabolic fluxes through pathways critical to health and disease as biomarkers for drug development and clinical diagnostics. In 2001, Dr. Hellerstein co-founded a biotech company, KineMed, Inc., that serves major pharmaceutical clients by making predictions of efficacy and toxicity to accelerate and reduce the cost of drug development. He currently serves as chairman of the KineMed, Inc. Scientific Advisory Board.
Michael D. Jensen is the Tomas J. Watson, Jr. Professor in Honor of Dr. Robert L. Frye at the Mayo College of Medicine, Rochester, MN. His research involves the study of obesity, body fat distribution, and fatty acid/energy metabolism, focusing specifically on the effects of obesity and body fat distribution on health and on the determinants of body fat distribution. Dr. Jensen served as president of the North American Association for the Study of Obesity, and currently serves as Senior Associate Editor of Diabetes.
Lee M. Kaplan, M.D., Ph.D., is director of the Obesity, Metabolism and Nutrition Institute at the Massachusetts General Hospital (MGH), and associate professor of medicine at Harvard Medical School (HMS). He is director of the fellowship program in Obesity Medicine and Nutrition at MGH, director of the Blackburn Course in Obesity Medicine at HMS, and chairman emeritus of the Campaign to End Obesity. He currently serves as Chair of the Obesity, Metabolism and Nutrition Section of the American Gastroenterological Association (AGA), and Chair of the Bariatric Surgery Section and Chair of the Clinical Committee of The Obesity Society. He is a member of the Advisory Council of the National Institute of Diabetes, Digestive and Kidney Diseases of the National Institutes of Health. Lee’s research is focused on the mechanisms by which the gastrointestinal tract regulates energy balance and metabolic function, and his group has pioneered the development and use of rodent models of weight loss surgery and gastrointestinal devices to explore these mechanisms. He is the author of more than 200 scientific and medical papers, including in The New England Journal of Medicine, Nature, Nature Genetics, Nature Medicine, and Science Translational Medicine. A graduate of Harvard College, Lee received his M.D. and Ph.D. from the Albert Einstein College of Medicine, and completed an internship and residency in internal medicine and a fellowship in gastroenterology at the Massachusetts General Hospital and Harvard Medical School.
Samuel Klein is the William H. Danforth Professor of Medicine, Director of the Center for Human Nutrition and Center for Applied Research Sciences, Chief of the Division of Geriatrics and Nutritional Sciences, and Medical Director of the Weight Management Program at Washington University School of Medicine in St. Louis. His interests include the mechanisms responsible for metabolic dysfunction associated with obesity and the therapeutic effects of weight loss. Dr. Klein served as president of the North American Association for the Study of Obesity and the American Society for Clinical Nutrition, and was inaugural chair of the Physiology of Obesity and Diabetes NIH study section.