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Physiology, Psychology, and Genetics of Obesity

• Jack A. Yanovski, MD, PhD, Head, Section on Growth and Obesity
• Joan C. Han, MD, Assistant Clinical Investigator
• Bonggi Lee, PhD, Visiting Fellow
• Roya Sherafat, MD, PhD, Special Volunteer
• Tania Condarco, MD, Fellow, Adult Endocrine Training Program
• Sarah Berger, PhD, Special Volunteer
• Melissa K. Crocker, MBA, MD, Special Volunteer
• Lauren B. Shomaker, PhD, Special Volunteer
• Sheila M. Brady, RN, FNP, Nurse Practitioner
• Arunabha Basu, BS, Postbaccalaureate Fellow
• Ryan Gardner, BA, Postbaccalaureate Fellow
• Amanda Krause, BS, Postbaccalaureate Fellow
• Mira Mooreville, BA, Postbaccalaureate Fellow
• Samantha Reina, BA, Postbaccalaureate Fellow
• Nicole Sedaka, BS, Postbaccalaureate Fellow
• Dezmond Taylor-Douglas, BS, Graduate Student

The prevalence of overweight and obesity in children and adults has tripled during the past 40 years (1). The alarming rise in body weight has likely occurred because the current environment affords easy access to calorie-dense foods and requires less voluntary energy expenditure. However, this 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, which suggests there are subgroups in the US with a uniquely high susceptibility to weight gain under the prevailing environmental conditions. The primary goal of the Section on Growth and Obesity 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 who have undergone intensive metabolic and behavioral phenotyping, we examine genetic and phenotypic factors predictive of progression to adult obesity in children who are in the "pre-obese" state, allowing characterization of phenotypes unconfounded by the impact of obesity itself. Once identified as linked to obesity, genetic variants that impair gene function are studied intensively. These approaches are expected to improve our ability to predict which children are at greatest risk for obesity and its comorbid conditions and to lead to more targeted, etiology-based prevention and treatment strategies for pediatric obesity.

Genetic factors important for childhood body weight regulation

To identify gene variants affecting body composition, we have been examining polymorphisms in genes involved in the leptin signaling pathway. Genes include FTO and those encoding proopiomelanocortin (POMC), the melanocortin 3 receptor (MC3R), brain-derived neurotrophic factor (BDNF), and histaminergic receptors 1 and 3. We are currently studying a variant MC3R that is associated with adiposity in children and appears to have functional significance for MC3R signal transduction. Children who were homozygous variant for both Thr6Lys and Val81Ile polymorphisms had significantly greater BMI-SD scores, fat mass, and body circumference measurements as well as higher plasma levels of insulin and leptin than unaffected or heterozygous children. In vitro studies subsequently found that signal transduction and protein expression were significantly lower for the double mutant MC3R than for the wild-type gene (Figure 1). Our ongoing studies attempt to understand the mechanisms by which these sequence alterations affect body weight. We found that children homozygous variant for both Thr6Lys and Val81Ile polymorphisms showed no deficits in energy expenditure but demonstrated hyperphagia in laboratory meal studies (Figure 2). The results were specific to function-altering mutations and not associated with other common polymorphisms that we identified in the MC3R. In collaboration with Heiner Westphal, we developed transgenic "knock-in" mice expressing the human wild-type and human double-mutant MC3R. Preliminary analyses suggest alterations in body composition consistent with our observations in humans. The mice will be intensively phenotyped over the next two years. We will also initiate a clinical investigation of lipolysis and lipogenesis in humans with these polymorphisms.

We also investigated the BDNF-TrkB pathway in relation to body mass in children. In a cohort of 328 children, age 3–19 years, we found that obese children exhibited significantly reduced BDNF levels; BMI, BMI-Z, and body fat were all negatively associated with BDNF levels. These data suggest that some obese individuals with low serum BDNF for age may have mutations that alter BDNF function. We therefore assessed the role of BDNF haploinsufficiency as a cause of obesity in patients with syndromes attributable to deletions in the vicinity of 11p14.1, where the human BDNF gene is located. In 33 subjects with the WAGR (Wilms tumor, aniridia, genitourinary, and renal abnormalities) syndrome who had heterozygous 11p deletions, ranging in size from 1.0–26.5 Mb, 19 had regions of deletion that involved the BDNF gene (BDNF^+/−). BDNF^+/− individuals had significantly greater body mass during childhood, starting at age 2, than those with intact BDNF (BDNF^+/+) (Figure 3).

We also investigated conditions such as Bardet Biedl and Alström syndromes that, based on mouse model data, may impair leptin receptor function. In collaboration with Leslie Biesecker's group, we found hyperleptinemia among patients with Bardet Biedl syndrome consistent with leptin receptor resistance (2), suggesting that defect-specific therapy may be possible. A new clinical protocol will investigate this possibility.

Physiology, metabolism, and psychology of childhood body weight regulation

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 that are most important for development of the complications of obesity in youth. Body composition, metabolic rate, insulin sensitivity, glucose disposal, energy intake at buffet meals, and genetic factors believed to regulate metabolic rate and body composition are examined. Psychological and behavioral factors, such as propensity to engage in binge-eating behavior (Figure 4), are also studied (3). Children are being followed longitudinally into adulthood. In two protocols, we study actual food consumption of children during meals, 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 found that eating in the absence of physiological hunger is a replicable trait that appears linked to obesity. We hypothesize that differences in these factors will 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 US population. A new clinical protocol based on a successful pilot study is examining the effects of a targeted interpersonal therapy intervention on body weight change in adolescents who endorse binge eating behaviors.

Our evaluations concentrating on binge eating behaviors in children suggest that such behaviors also are associated with adiposity in children. We also found that binge eating and dieting behaviors may predict future weight gain in children at risk for obesity; children reporting binge-eating behaviors such as loss of control (LOC) over eating gained, on average, an 2.4 kg of weight per year more than children who did not engage in binge eating. Our data suggest that children endorsing binge eating consume more calories during meals. Actual intake during buffet meals averaged 400 kcal more in children who engaged in binge eating, but despite their greater intake, such children reported shorter-lived satiety than children not exhibiting binge eating episodes. The ability to consume large quantities of palatable foods, especially when coupled with decreased subsequent satiety, may play a role in the greater weight gain found in binge-eating children. These data also suggest that interventions targeting disordered eating behaviors may be useful in preventing excessive fat gain in children prone to obesity and have led to ongoing trials of preventative strategies related to binge eating. Because binge eating appears to be a heritable trait, we initiated studies to investigate potential genetic factors linked to loss of control over eating. For example, we previously reported that, among 229 youth aged 6–19 y who were genotyped for the FTO single-nucleotide polymorphism (SNP) rs9939609, subjects with at least one A allele (67.7%) had significantly greater BMI, BMI z scores, and fat mass. Of the AA/AT subjects, 34.7% reported LOC compared with 18.2% of the TT subjects. AA/AT subjects consumed a greater percentage of energy from fat than did the TT subjects. We recently found preliminary evidence of a link between the FTO SNP rs9939609 and eating in the absence of hunger, which we pursue further in the next year.

We examined the short- and long-term stability of the components of metabolic syndrome. We found that leptin is an important predictor of weight gain in children: when followed longitudinally, those exhibiting high leptin levels gain more weight than those with lower leptin levels. We documented that hyperinsulinemia is positively related to energy intake in non-diabetic, obese children. We also examined the relationship between depressive symptomatology and insulin resistance in children and adolescents, finding strong associations both cross-sectionally and prospectively (4) between depressive symptoms and insulin resistance, independent of body weight. These associations suggest mechanisms whereby insulin resistance may contribute to excessive weight gain in children and have informed some of our treatment approaches to pediatric obesity.

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

Given the rapid increase in the prevalence of obesity, the development of treatments for obesity in children and adults is urgently needed. In multiple clinical protocols, we have examined approaches for the prevention and treatment of excessive body weight. We completed a pilot study demonstrating that severely obese adolescents can lose weight when enrolled in a comprehensive weight-management program that includes the gastrointestinal lipase inhibitor orlistat as an adjunct to a behavioral modification program. We recently completed a placebo-controlled randomized trial, studying whether the weight loss of African American and Caucasian children and adolescents who have obesity-related comorbidities was improved by the use of 120 mg TID orlistat. 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 frequently sampled intravenous glucose tolerance test (FSIGT), fasting lipids, pulse, and blood pressure before and after treatment. 200 adolescents, 65% female, 61% African American, mean age14.6±0.10y SEM, BMI 41.7±0.6 kg/m² (range 27-87 kg/m²) were studied. 85.5% of subjects completed the trial. Adolescents treated with orlistat lost significantly more weight, BMI units, and fat mass. Although pulse and blood pressure decreased during the trial, orlistat treatment did not significantly alter these variables. Similarly, HOMA-IR, SI 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 comorbidities. Both AST (+1.8±0.9 vs. -1.08±0.9) and ALT (+1.3±1.1 vs. -2.4±1.2) unexpectedly increased significantly with orlistat treatment. We concluded that orlistat added to a behavioral program significantly improved weight loss over a 6-month interval, but had little impact on obesity-related co-morbid conditions in obese adolescents.

A second now-completed study (5) examined the mechanism by which metformin may affect the body weight of younger children who have hyperinsulinemia and are therefore 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 1000 mg b.i.d. metformin, administered with meals, in severely obese children (6–12y) who manifested hyperinsulinemia and insulin resistance. Subjects participated in a monthly dietitian-administered weight reduction program. Body mass index and body composition (by air displacement plethysmography), glucose homeostasis (by HOMA-IR), and lipids were measured before and after 6-months' treatment.  100 obese children (60% female, 11% Hispanic, 3% Asian, 40% African American), mean age 10.2±1.5y, with mean BMI 34.6±6.6 kg/m² (range 23-58 kg/m²) were enrolled between October 2000 and April, 2007. 85% of subjects (84% given metformin and 86% given placebo) completed the trial.  BMI, BMI-Z score, and body fat mass of children randomized to metformin decreased to a significantly greater extent than in the placebo-treated group. Serum glucose and HOMA-IR also decreased more in metformin-treated than in placebo-treated children. We concluded that metformin, added to a monthly behavioral program, significantly improved weight loss and insulin resistance over a 6-month interval in severely obese, insulin-resistant children.

A third clinical trial in adults examined the role dietary calcium plays in body weight. 340 overweight (BMI 25 to <30 kg/m2) and obese (BMI ≥30 kg/m2) adults were randomized to take calcium carbonate (elemental calcium, 1500 mg/d, n = 170) or placebo, n = 170) with meals for two years. Seventy-five percent of participants completed the trial (78% received calcium; 73% received placebo). There were no statistically or clinically significant differences between the calcium and placebo groups in change in body weight, BMI, or body fat mass. Parathyroid hormone concentrations decreased in the calcium group compared with the placebo group. We concluded that dietary supplementation with elemental calcium, 1500 mg/d, for 2 years had no statistically or clinically significant effects on weight in overweight and obese adults. Thus, calcium supplementation is unlikely to have clinically significant efficacy as a weight-gain preventive measure in such patients.

A fourth recently completed study examined the role central nervous system histamine plays in controlling food intake at meals.  Additional studies that are anticipated to begin next year will test specific therapies directed at ameliorating inadequate leptin signaling, specifically in conditions that are marked by leptin receptor hypofunction, and test methods to reduce insulin resistance in adolescents at risk for Type 2 Diabetes.

Additional Funding

• Prader-Willi Syndrome Association (USA) Best Idea Grant for Hyperphagia Research
• NIH Clinical Center "Bench to Bedside" Award: Fat Metabolism and Function-Altering Polymorphisms in MC3R 2011–2013
• NIH Clinical Center "Bench to Bedside" Award: Depression and Insulin Resistance in Adolescent Girls 2011–2013

Publications

• Yanovski SZ, Yanovski JA. Obesity prevalence in the United States—up, down, or sideways? N Engl J Med 2011;364:987-989.
• Myers MG, Jr., Heymsfield SB, Haft C, Kahn BB, Laughlin M, Leibel RL, Tschop MH, Yanovski JA. Challenges and opportunities of defining clinical leptin resistance. Cell Metab 2012;15:150-156.
• Tanofsky-Kraff M, Shomaker LB, Olsen C, Roza CA, Wolkoff LE, Columbo KM, Raciti G, Zocca JM, Wilfley DE, Yanovski SZ, Yanovski JA. A prospective study of pediatric loss of control eating and psychological outcomes. J Abnorm Psychol 2011;120:108-118.
• Shomaker LB, Tanofsky-Kraff M, Stern EA, Miller R, Zocca JM, Field SE, Yanovski SZ, Hubbard VS, Yanovski JA. Longitudinal study of depressive symptoms and progression of insulin resistance in youth at risk for adult obesity. Diabetes Care 2011;34:2458-2463.
• Yanovski JA, Krakoff J, Salaita CG, McDuffie JR, Kozlosky M, Sebring NG, Reynolds JC, Brady SM, Calis KA. Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial. Diabetes 2011;60:477-485.

Collaborators

• Leslie Biesecker, MD, Genetic Disease Research Branch, NHGRI, Bethesda, MD
• Andrew Butler, PhD, The Scripps Research Institute, La Jolla, CA
• Kong Chen, PhD, Clinical Endocrinology Branch, NIDDK, Bethesda, MD
• Samuel Cushman, PhD, Diabetes Branch, NIDDK, Bethesda, MD
• Myles Faith, PhD, University of Pennsylvania School of Medicine, Philadelphia, PA
• I. Sadaf Farooqi, MD, Cambridge Institute for Medical Research, Cambridge, UK
• Katherine Flegal, MPH, PhD, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD
• Oksana Gavrilova, PhD, Mouse Metabolism Core Laboratory, NIDDK, Bethesda, MD
• 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
• Rudolph L. Leibel, MD, Columbia University College of Physicians and Surgeons, New York, NY
• Stephen O'Rahilly, MD, Cambridge Institute for Medical Research, Cambridge, UK
• Dale A. Schoeller, PhD, University of Wisconsin, Madison, WI
• Eric Stice, PhD, Oregon Research Institute, Eugene, OR
• Marian Tanofsky-Kraff, PhD, Uniformed Services University of the Health Sciences, Bethesda, MD
• George R. Uhl, MD, PhD, Molecular Neurobiology Branch, NIDA, Baltimore, MD
• B. Timothy Walsh, PhD, Columbia University College of Physicians and Surgeons, New York, NY
• Heiner Westphal, MD, Program on Genomics of Differentiation, NICHD, Bethesda, MD
• Denise E. Wilfley, PhD, Washington University School of Medicine, St. Louis, MO
• Susan Z. Yanovski, MD, Obesity and Eating Disorders Program, NIDDK, Bethesda, MD

Contact

For further information, contact yanovskj@mail.nih.gov or visit sgo.nichd.nih.gov.

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