Physiology, Psychology, and Genetics of Obesity

Jack A. Yanovski, MD, PhD, Head, Unit on Growth and Obesity
Joan Han, MD, Clinical Fellow, Endocrine Training Program
Mary Roberts, MD, Clinical Fellow, Endocrine Training Program
Lisa Yanoff, MD, Clinical Fellow, Endocrine Training Program
David Savastano, PhD, Postdoctoral Fellow
Sheila Brady, RN, FNP, Nurse Practitioner
Diane Adler-Wailes, MS, Biologist
Jenna Checchi, BS, Postbaccalaureate Fellow
Jennifer Gustafson, BS, Postbaccalaureate Fellow
Rebecca Levinn, BA, Postbaccalaureate Fellow
Lisa Ranzenhofer, BS, Postbaccalaureate Fellow
Ethan Sanford, BA, Postbaccalaureate Fellow
Rachel Sorg, BA, Postbaccalaureate Fellow

The prevalence of overweight and obesity in children and adults has tripled during the past 30 years. The alarming rise in body weight has likely occurred because the current environment affords easy access to calorie-dense foods and requires less energy expenditure. However, the same environment leads to obesity only in those individuals whose body weight–regulatory systems are not able to control body adiposity with sufficient precision in our high-calorie/low-activity environment, thus suggesting that some subgroups in the United States have a uniquely high susceptibility to weight gain. Our goal is to elucidate the genetic underpinnings of the metabolic and behavioral endophenotypes that contribute to the development of obesity in children. Using our unique longitudinal cohort of children at risk for adult obesity, we examine genetic and phenotypic factors predictive of progression to adult obesity in children in the “pre-obese” state, allowing characterization of phenotypes unconfounded by the impact of obesity itself. We focus on genetic variants linked to obesity that impair gene function. We expect our approaches to improve our ability to predict which children are at greatest risk for obesity and its co-morbid conditions and to lead to more targeted, etiology-based prevention and treatment strategies for pediatric obesity.

Molecular studies of factors important for childhood body weight regulation

Adler-Wailes, Gustafson, Han, Levinn, Ranzenhofer, Sanford, Savastano, Yanovski J; in collaboration with Aguilera, Farooqi, Gavrilova, Gordon, Leibel, Liu, Lu, Kleinman, O’Rahilly, Tanofsky-Kraff, Tessarollo, Uhl, Westphal

To identify gene variants affecting body composition, we have been examining polymorphisms in genes involved in the leptin signaling pathway. Genes include proopiomelanocortin (POMC), the melanocortin 3 receptor (MC3R), brain-derived neurotrophic factor (BDNF), and the type 2 neurotrophin receptor TrkB. We previously studied genes important for energy expenditure, such as the mitochondrial uncoupling proteins, and genes potentially involved in cortisol metabolism that may affect intra-abdominal adipose tissue, such as 11-beta-hydroxysteroid dehydrogenase. We are currently studying a variant MC3R that is associated with adiposity in children and appears to have functional significance for MC3R signal transduction (Feng et al., Diabetes 2005;54:2663). Children who were homozygous-variant for both the polymorphisms Thr6Lys and Val81Ile had significantly greater BMI (body mass index)-SD score, fat mass, and body circumference measurements and higher plasma levels of insulin and leptin than children who either did not bear the variant or were heterozygous. In vitro studies subsequently found that MC3R expression was significantly lower for the double mutant. Ongoing studies are attempting to understand the mechanisms by which these sequence alterations may affect body weight. In collaboration with Heiner Westphal, we developed transgenic knock-in mice expressing the human non-mutant and human double mutant MC3R and will study them over the next two years.

We have also recently investigated the BDNF-TrkB pathway as it relates to body mass in children. We measured serum BDNF in 328 children age 3 to 19, many of whom suffered from extreme obesity. BDNF was significantly lower in overweight children; multiple regression analyses with log-BDNF as the dependent variable showed that BMI, BMI Z-score, and body fat were all negatively associated with BDNF. The data suggest that some obese individuals with low serum BDNF for age and platelet count may have mutations that alter BDNF function. In collaboration with Sadaf Farooqi and Stephen O’Rahilly, we found that individuals with heterozygous TrkB mutations do not have unusually high circulating BDNF, and we identified a child with hyperphagia and severe obesity associated with functional loss of one copy of the BDNF gene. The child had a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF, but we observed monoallelic expression in peripheral lymphocytes. The child’s serum BDNF was markedly lower than in age- and BMI-matched control subjects. Functional haploinsufficiency for BDNF was thus associated with increased ad libitum food intake and severe early-onset obesity. Our findings provide evidence for the role of BDNF in human energy homeostasis.

with syndromes attributable to deletions in the vicinity of 11p14.1, which is where the human BDNF gene is located. Using a comparative genomic hybridization approach verified with PCR-based assays, we examined genotype-phenotype relationships in patients with 11p deletion syndromes such as WAGR (Wilms tumor, aniridia, genitourinary, and renal abnormalities) syndrome. In 33 subjects with heterozygous 11p deletions ranging in size from 1.0 to 26.5 Mb, 19 had regions of deletion that involved the BDNF gene (BDNF^+/−). Compared with those with intact BDNF (BDNF^+/+), BDNF^+/− individuals had significantly greater body mass during childhood, starting at age 2, and 100 percent of BDNF^+/− individuals were overweight by age 10 compared with only 20 percent of BDNF^+/+. Parent-completed hyperphagia questionnaires suggested significantly greater hyperphagic behavior, drive, and severity for BDNF ^+/− than for BDNF^+/+. Mean serum BDNF was approximately 50 percent lower among BDNF^+/−. The result remained statistically significant after adjustments for sex, current age, BMI, and platelet count. We then examined the centromeric and telomeric boundaries of each individual’s deletion and observed no association between the extent of subjects’ centromeric deletion and childhood overweight. However, analysis of the telomeric deletion boundaries indicated the presence of a critical region for pediatric-onset overweight within 80 kb of the BDNF exon. One overweight subject had deletion of BDNF exons I through III but preservation of subsequent BDNF exons. Each subject who maintained normal weight during childhood had a deletion that did not involve BDNF. These findings suggest that BDNF haploinsufficiency in patients with WAGR syndrome leads to pediatric-onset obesity. In the coming year, we plan to undertake a full characterization of the energy intake and expenditure of subjects with WAGR syndrome and other 11p deletion syndromes.

El-Gharbawy A, Adler-Wailes DC, Mirch MC, Theim KR, Ranzenhofer LM, Tanofsky-Kraff M, Yanovski JA. Serum brain derived neurotrophic factor concentrations in lean and overweight children and adolescents. J Clin Endocrinol Metab 2006;91:3548-3552.
Gray J, Yeo GSH, Cox JJ, Keogh JM, Morton J, Adlam A, Yanovski JA, El Gharbawy A, Han JC, Tung YCL, Hodges J, Raymond FL, O’Rahilly S, Farooqi IS. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the BDNF gene. Diabetes 2006;55:3366-3371.
Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, Adler-Wailes DC, Sanford EL, Lacbawan FL, Uhl GR, Rennert OM, Yanovski JA. Brain derived neurotrophic factor and obesity in WAGR syndrome. New Engl J Med 2008;359:918-927.

Physiology, metabolism, and psychology of childhood body weight regulation

Han, Roberts, Savastano, Brady, Gustafson, Sorg, Checchi, Yanovski J; in collaboration with Troendle, Malley, Chen K, Yanovski S, Gorbach, Hubbard, Reynolds, Kozlosky, Sebring, Salaita, Denkinger, Drinkard, Faith, Levine, Cox, Rolls, Schoeller, Tanofsky-Kraff, Walsh, Wilfley

Our studies focus on understanding the physiological, psychological, and metabolic factors that place children at risk for undue weight gain. As part of these studies, we have examined how best to measure psychopathology, insulin sensitivity, changes in body composition, energy intake, and energy expenditure in children. We have found that leptin is an important predictor of weight gain in children. In fact, children with high leptin whom we have followed longitudinally experience accelerated weight gain. Recent investigations documented a greater prevalence of fractures and musculoskeletal complaints in significantly overweight children as well as a greater degree of valgus misalignment of the lower extremities that may contribute both to difficulties with exercise and further weight gain in overweight youth. We have also found marked effects of obesity on quality of life in adolescents.

Our evaluations concentrating on binge-eating behaviors in children suggest that such behaviors also are associated with adiposity in children. We found that binge-eating and dieting behaviors may predict future weight gain in children at risk for overweight. Over an observation period of about 4 years, children reporting binge-eating behaviors gained, on average, an additional 15 percent more fat mass than non–binge-eating children. Our recent data also suggest that children endorsing binge eating consume more energy during meals. Actual intake during buffet meals averaged 400 kcal more in children indulging in binge eating, but despite their greater intake, such children reported shorter-lived satiety than children without binge-eating episodes. The ability to consume large quantities of palatable foods, especially when coupled with a decrease in subsequent satiety, may play a role in the greater weight gain observed in binge-eating children. The data also suggest that interventions targeting disordered eating behaviors may potentially be useful in preventing excessive fat gain in children prone to obesity.

In two ongoing protocols, we study normal-weight children and adolescents, children who are already obese, and the non-obese children of obese parents in order to determine the factors most important for development of the complications of obesity in youth. We examine body composition, metabolic rate, insulin sensitivity, glucose disposal, energy intake at buffet meals, and genetic factors believed to regulate metabolic rate and body composition. We also study psychological and behavioral factors, such as propensity to engage in binge-eating behavior. In two longitudinal protocols, we study actual food consumption of children during meals in order to elucidate differences in the calorie and macronutrient content of meals and the circulating hormones related to hunger and satiety in those who either endorse binge-eating behaviors or report no such behaviors. We hypothesize that differences in these factors predict the development of obesity in the populations studied and may be of great importance in developing rational approaches for the prevention and treatment of obesity in the diverse U.S. population. A new clinical protocol based on a successful pilot study will examine the effects of a targeted interpersonal therapy intervention on body weight change in adolescents who endorse binge-eating behaviors.

Fleisch AF, Agarwal N, Roberts MD, Han JC, Theim KR, Vexler A, Troendle J, Yanovski SZ, Yanovski JA. Influence of serum leptin on weight and body fat growth in children at high risk for adult obesity. J Clin Endocrinol Metab 2007;92:948-954.
Mirch M, McDuffie J, Yanovski S, Schollnberger M, Tanofsky-Kraff M, Theim K, Krakoff, J, Yanovski JA. Effects of binge eating on satiation, satiety, and energy intake of overweight children. Am J Clin Nutr 2006;84:732-738.
Robotham DR, Schoeller DA, Mercado AB, Mirch MC, Theim KR, Reynolds JC, Yanovski JA. Estimates of body fat in children by Hologic QDR-2000 and QDR-4500A dual-energy X-ray absorptiometers compared with deuterium dilution. J Pediatr Gastroenterol Nutr 2006;42:331-335.
Tanofsky-Kraff M, Cohen ML, Yanovski SZ, Cox C, Theim KR, Keil M, Reynolds JC, Yanovski JA. A prospective study of psychological predictors of body fat gain among children at high risk for adult obesity. Pediatrics 2006;117:1203-1209.
Tanofsky-Kraff M, Goossens L, Eddy KT, Ringham R, Goldsmith A, Yanovski SZ, Braet C, Marcus MD, Wilfley DE, Olsen C, Yanovski JA. A multi-site investigation of binge eating behaviors in children and adolescents. J Consult Clin Psychol 2007;75:901-913.

Treatment of obesity and the co-morbid conditions associated with obesity

Yanoff, Roberts, Savastano, Brady, Adler-Wailes, Glasofer, Sorg, Gustafson, Checchi, Yanovski J; in collaboration with Hubbard, Krakoff, Reynolds, Calis, Kozlosky, Sebring, Salaita, Denkinger, Drinkard, Booth, Levine, Rolls, Schoeller, Tanofsky-Kraff

Given the rapid increase in the prevalence of obesity, the development of treatments for obesity in childhood is urgently needed. In three ongoing clinical protocols, we are studying approaches for the control of body weight in children. We completed a pilot study demonstrating that severely overweight adolescents can lose weight when enrolled in a comprehensive weight management program that includes the gastrointestinal lipase inhibitor orlistat as an adjunct to a behavior-modification program. We recently completed a placebo-controlled randomized trial to determine whether the use of orlistat 120 mg t.i.d. improved the weight loss of African American and Caucasian children and adolescents with obesity-related co-morbidities. Subjects participated in a 12-week weight reduction program. We compared body weight and body composition (by DXA and air displacement plethysmography), glucose homeostasis by the frequently sampled intravenous glucose tolerance test (FSIGT), fasting lipids, pulse, and blood pressure before and after treatment. The study group consisted of 200 adolescents, 65 percent female, 61 percent African American, mean age 14.6 years, and BMI 41.7 kg/m² (range 27–87 kg/m²). At baseline, subjects randomized to orlistat or placebo did not differ significantly in age, sex, race, BMI, or fat mass. Adolescents treated with orlistat lost more weight, BMI units, and fat mass. Although subjects’ pulse and blood pressure decreased during the trial, orlistat treatment played no role in the reduction. Similarly, HOMA-IR (homeostasis model assessment of insulin resistance), SI (insulin sensitivity index) by FSIGT, Apo B, total and LDL cholesterol, and triglycerides decreased in proportion to weight loss, but orlistat use was not associated with significant reductions in any of these obesity-related laboratory co-morbidities. Orlistat treatment did not significantly alter concentrations of the fat-soluble vitamins 25OH vitamin D, vitamin A, and vitamin E. Both AST (aspartate aminotransferase) and ALT (alanine amino transferase) unexpectedly increased significantly with orlistat treatment. We concluded that a behavior-modification program that includes orlistat significantly improved weight loss over a 6-month interval but had little impact on obesity-related co-morbid conditions in overweight adolescents.

A second study examined the mechanism by which metformin may affect the body weight of younger children who have hyperinsulinemia and therefore are at risk for later development of type 2 diabetes. We conducted a single-center, 6-month, randomized, double-blind, placebo-controlled trial of the effects of metformin, 1,000 mg b.i.d. administered with meals, in severely overweight children (age 6 to 12 years) who manifested hyperinsulinemia and insulin resistance. Subjects participated in a monthly dietitian-administered weight reduction program. We measured BMI and body composition (by air displacement plethysmography), glucose homeostasis (by HOMA-IR), and lipids before and after 6 months’ treatment. We enrolled 100 overweight children (60 percent female, 11 percent Hispanic, 3 percent Asian, 40 percent African American), mean age 10.2±1.5 years, with mean BMI 34.6±6.6 kg/m² (range 23–58 kg/m²) between October 2000 and April 2007. Compared with placebo-treated children, those randomized to metformin evidenced a decrease in BMI, BMI Z-score, and body fat mass to a significantly greater extent. Serum glucose, HOMA-IR, and total cholesterol also declined more in metformin-treated than in placebo-treated children. We concluded that metformin, added to a monthly behavior-modification program, significantly improved weight loss, insulin resistance, and cholesterol over a 6-month interval in severely overweight, insulin-resistant children. A third ongoing study examines the role played by central nervous system histamine in controlling food intake at meals. Subjects are randomized to take placebo or one of several doses of betahistine, and we measure food intake at meals.

Drinkard B, Roberts MD, Ranzenhofer LM, Han JC, Yanoff LB, Merke DP, Savastano DM, Brady S, Yanovski JA. Oxygen-uptake efficiency slope as a determinant of fitness in overweight adolescents. Med Sci Sports Exerc 2007;39:1811-1816.
Glasofer DR, Tanofsky-Kraff M, Eddy KT, Yanovski SZ, Theim KR, Mirch MC, Ghorbani S, Ranzenhofer LM, Haaga D, Yanovski JA. Binge eating in overweight treatment-seeking adolescents. J Pediatr Psychol 2007;32:95-105.
Han JC, Rutledge MS, Kozlosky M, Salaita CG, Gustafson JK, Keil MF, Fleisch AF, Roberts MD, Ning C, Yanovski JA. Insulin resistance, hyperinsulinemia, and energy intake in overweight children. J Pediatr 2008;152:612-617.
Han JC, Yanovski JA. Intensive therapies for the treatment of pediatric obesity. In: Jelalian E, Steele RC, eds. Handbook of Child and Adolescent Obesity. Springer, 2007;241-260.

Collaborators

Greti Aguilera, MD, Program in Developmental Endocrinology and Genetics, NICHD, Bethesda, MD
Sarah Booth, PhD, USDA, Human Nutrition Research Center on Aging at Tufts University, Cambridge, MA
Karim Calis, Pharm D, Pharmacy Department, Clinical Center, NIH, Bethesda, MD
Kong Chen, PhD, Clinical Endocrinology Branch, NIDDK, Bethesda, MD
Christopher Cox, PhD, The Johns Hopkins University, Baltimore, MD
Blakeley Denkinger, MPH, RD, Nutrition Department, Clinical Center, NIH, Bethesda, MD
Bart Drinkard, PT, Rehabilitation Medicine Department,Clinical Center, NIH, Bethesda, MD
Myles Faith, PhD, University of Pennsylvania School of Medicine, Philadelphia, PA
I. Sadaf Farooqi, MD, Cambridge Institute for Medical Research, Cambridge, UK
Oksana Gavrilova, PhD, Mouse Metabolism Core Laboratory, NIDDK, Bethesda, MD
Alexander Gorbach, PhD, Laboratory of Bioengineering and Physical Science, NIBIB, Bethesda, MD
Leslie Gordon, MD, PhD, Hasbro Children’s Hospital, Providence, RI
Van S. Hubbard, MD, PhD, Division of Nutritional Research Coordination, NIDDK, Bethesda, MD
Joel E. Kleinman, MD, PhD, Clinical Brain Disorders Branch, NIMH, Bethesda, MD
Merel Kozlosky, MS, RD, Nutrition Department, Clinical Center, NIH, Bethesda, MD
Jonathan Krakoff, MD, Phoenix Epidemiology and Clinical Research Branch, NIDDK, Phoenix, AZ
Rudolph L. Leibel, MD, Columbia University College of Physicians and Surgeons, New York, NY
James Levine, MD, PhD, Mayo Clinic, Rochester, MN
Qing-Rong Tim Liu, PhD, Molecular Neurobiology Branch, NIDA, Baltimore, MD
Bai Lu, PhD, Program in Developmental Neuroscience, NICHD, Bethesda, MD
James D. Malley, PhD, Mathematical and Statistical Computing Laboratory, CIT, NIH, Bethesda, MD
Stephen O’Rahilly, MD, Cambridge Institute for Medical Research, Cambridge, UK
James Reynolds, MD, Nuclear Medicine, Clinical Center, NIH, Bethesda, MD
Barbara J. Rolls, PhD, Pennsylvania State University, University Park, PA
Christine Salaita, MS, RD, Nutrition Department, Clinical Center, NIH, Bethesda, MD
Dale A. Schoeller, PhD, University of Wisconsin, Madison, WI
Nancy Sebring, MEd, RD, Nutrition Department, Clinical Center, NIH, Bethesda, MD
Marian Tanofsky-Kraff, PhD, USUHS Department of Psychology, Bethesda, MD
Lino Tessarollo, PhD, NCI Frederick Mouse Cancer Genetics Program, Frederick, MD
James Troendle, PhD, Division of Epidemiology, NICHD, Bethesda, MD
George R. Uhl, PhD, MD, Molecular Neurobiology Branch, NIDA, Baltimore, MD
B. Timothy Walsh, PhD, Columbia University College of Physicians and Surgeons, New York, NY
Heiner Westphal, MD, Program in Genomics of Differentiation, NICHD, Bethesda, MD
Denise E. Wilfley, PhD, Washington University School of Medicine, St. Louis, MO
Alexander F. Wilson, PhD, Inherited Disease Research Branch, NHGRI, Baltimore, MD
Susan Z. Yanovski, MD, Obesity and Eating Disorders Program, NIDDK, Bethesda, MD

For further information, contact yanovskj@mail.nih.gov or visit http://ugo.nichd.nih.gov.