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Physiology, Psychology, and Genetics of Obesity

• Jack A. Yanovski, MD, PhD, Head, Section on Growth and Obesity
• Joo Yun Jun, PhD, Postdoctoral Fellow
• Andrew Demidowich, MD, Adult Endocrine Training Program Fellow
• Ovidiu Galescu, MD, Pediatric Endocrine Training Program Fellow
• Britni R. Belcher, PhD, Special Volunteer
• Nichole Kelly, PhD, Special Volunteer
• Rachel Miller-Radin, MA, Special Volunteer
• Natasha A. Schvey, PhD, Special Volunteer
• Lisa Shank, MA, Special Volunteer
• Anna Vannucci, MA, Special Volunteer
• Sheila M. Brady, RN, FNP, Nurse Practitioner
• Robin Roberson, MS, Technician
• Dezmond Taylor-Douglas, BS, Graduate Student
• Anne Altschul, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Nicket Dedhia, BA, Postbaccalaureate Intramural Research Training Award Fellow
• Rim D. Mehari, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Ira S. Tigner, MS, Technical Intramural Research Training Award Fellow

The prevalence of overweight and obesity in children and adults has tripled during the past 40 years. 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, such an 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 U.S. with a uniquely high susceptibility to weight gain under the prevailing environmental conditions. Our primary goal is to elucidate the genetic underpinnings of the metabolic and behavioral endo-phenotypes 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 they are identified as linked to obesity, we study intensively genetic variants that impair gene function. We expect that these approaches will improve our ability to predict which children are at greatest risk for obesity and its comorbid conditions and will 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 the leptin receptor (LEPR), FTO (fat mass and obesity-associated gene), and those encoding proopiomelanocortin (POMC), the melanocortin 3 receptor (MC3R), the melanocortin 4 receptor (MC4R), and brain-derived neurotrophic factor (BDNF) (Reference 1). 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 C17A and G241A polymorphisms have significantly greater fat mass and higher plasma levels of insulin and leptin than unaffected or heterozygous children and appear to eat more at laboratory test meals (Figure 1). In vitro studies subsequently found that signal transduction and protein expression were significantly lower for the double mutant MC3R. Our ongoing studies attempt to understand the mechanisms by which these sequence alterations may affect body weight. Transgenic 'knock-in' mice expressing the human wild-type and human double-mutant MC3R were therefore developed. Preliminary analyses suggest alterations in body composition consistent with our observations in humans, but show evidence of surprising metabolic health despite their obesity (Figure 2). We will continue to phenotype these mice intensively over the next two years. We have also initiated 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 had significantly lower BDNF; BMI, BMI-Z, and body fat were all negatively associated with BDNF. The 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^+/−). Compared with those with intact BDNF (BDNF^+/+), BDNF^+/− individuals had significantly greater body mass during childhood, starting at age two (Figure 3). A recent investigation examined common polymorphisms in the BDNF gene region. We examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We found that the minor C allele of rs12291063 is associated with significantly lower human ventromedial hypothalamic BDNF expression and greater adiposity in both adult and pediatric cohorts. We also demonstrated that the major T allele for rs12291063 binds to heterogeneous nuclear ribonucleoprotein D0B, a transcriptional regulator, knockdown of which disrupts transactivation by the T allele (Reference 2). Binding and transactivation functions are both disrupted by substitution of T with the minor C allele. The findings provide a rationale to pursue augmentation of BDNF expression and BDNF receptor signaling as targeted obesity treatments for individuals with the rs12291063 CC genotype.

Physiology, metabolism, and psychology of childhood body weight regulation

Our studies are directed at understanding the physiological, psychological, and metabolic factors that place children at risk for undue weight gain. As part of these studies, we examined how best to measure eating-related psychopathology, insulin sensitivity, changes in body composition, energy intake, and energy expenditure in children, and studied 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: those with high leptin gain even more weight when followed longitudinally. We also documented that hyperinsulinemia is positively related to energy intake in non-diabetic, obese children, leading to treatment studies to reduce hyperinsulinemia (see below). We also examined the relationship between depressive symptomatology and insulin resistance in children and adolescents, finding strong associations both cross-sectionally and prospectively between depressive symptoms and insulin resistance independent of body weight. The 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 (described below).

Our evaluations concentrating on binge-eating behaviors in children suggest that such behaviors also are associated with adiposity in children and abnormalities in metabolism (Reference 3). We found that binge-eating 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 additional 2.4 kg of weight per year compared with non-binge-eating children. Our data also suggest that children endorsing binge eating consume more energy during meals. Actual intake during buffet meals averaged 400 kcal more in children with 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 decreased subsequent satiety, may play a role in the greater weight gain found in binge-eating children. We demonstrated that, among a cohort of 506 lean and obese youth, youth with LOC eating had significantly higher serum leptin than those without LOC episodes, even after adjusting for adiposity and other relevant covariates. The 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 also initiated studies to investigate potential genetic factors linked to LOC over eating. For example, we previously reported among 229 youth, aged 6–19 years, who were genotyped for FTO SNP rs9939609, subjects with at least one A allele (67.7%) had significantly greater BMI, BMI Z-scores, and fat mass. We also found preliminary evidence of a link between FTO SNP rs9939609 and eating in the absence of hunger.

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. We examine body composition, leptin concentration, metabolic rate, insulin sensitivity, glucose disposal, energy intake at buffet meals, and genetic factors believed to regulate metabolic rate and body composition. Psychological and behavioral factors, such as propensity to engage in binge-eating behavior (Figure 4), are also studied. 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 thus may be of great importance in developing rational approaches for the prevention and treatment of obesity in the diverse US population.

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, yet current pharmacologic approaches are extremely limited for both children and adults (Yanovski SZ and Yanovski JA, JAMA 2014;311:74-86). In several clinical protocols, we 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 also 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 orlistat 120 mg three times a day. 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 age±SEM 14.6±0.10y, 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 significantly during the trial, orlistat treatment did not significantly alter these variables. Similarly, HOMA-IR (homeostasis model assessment–insulin resistance), SI (insulin resistance) by FSIGT, apolipoprotein B, total and LDL–cholesterol, and triglycerides declined significantly in proportion to weight loss, but orlistat use was not associated with significant reductions in any of these obesity-related laboratory comorbidities. Both aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are used to measure liver function, 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 obesity treatment study 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 metformin, 1000 mg twice a day, 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. Compared with placebo-treated children, the BMI, BMI Z-score, and body fat mass of those randomized to metformin declined to a significantly greater extent. Serum glucose and HOMA-IR also declined significantly more in metformin-treated than in placebo-treated children. Compared with placebo, metformin treatment also elicited significant reductions from baseline in the mean energy intake independently of changes in body composition. Metformin also significantly decreased ratings of hunger and increased ratings of fullness after the pre-meal load (Reference 4). The data suggest that lower perceived hunger resulting in diminished food intake are among the mechanisms by which metformin treatment reduces body weight in overweight children with hyperinsulinemia. 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 examined the efficacy of two diets among Hispanic children and adolescents, where the prevalence of obesity and insulin resistance is considerably greater than in non-Hispanic white children. A low-glycemic load diet (LGD) has been proposed as an effective dietary intervention for pediatric obesity, but no published study had examined the effects of an LGD in obese Hispanic children. We compared the effects of an LGD and a low-fat diet (LFD) on body composition and components of metabolic syndrome in obese Hispanic youth. Obese Hispanic children (7–15 years of age) were randomly assigned to consume an LGD or an LFD in a two-year intervention program. Body composition and laboratory assessments were obtained at baseline and 3, 12, and 24 months after intervention. In the 113 children who were randomly assigned, 79% of both groups completed three months of treatment and 58% of LGD and 55% of LFD subjects attended 24-month follow-up. Compared with the LFD, the LGD decreased the glycemic load per kilocalories of reported food intakes in participants at 3 months. Both groups had a significant reduction in BMI Z-score and improved waist circumference and systolic blood pressure at 3, 12, and 24 months after intervention. However, there were no significant differences between groups for changes in BMI, insulin resistance, or components of metabolic syndrome. We thus found no evidence that an LGD and an LFD differ in efficacy for the reduction of BMI or aspects of metabolic syndrome in obese Hispanic youth. Both diets reduced the BMI Z-score when prescribed in the context of a culturally adapted, comprehensive weight-reduction program.

A fourth recently completed study examined prevention of weight gain using interpersonal therapy in adolescents reporting loss of control eating behaviors (Reference 5). An additional ongoing study tests methods to reduce insulin resistance in adolescents at-risk for type 2 diabetes. This protocol completed accrual in 2014 and will complete follow-up in 2015.

A novel intervention to be studied in the next three years with a randomized-controlled trial involving the use of colchicine to ameliorate inflammation associated with obesity and thus improve its complications.

Additional Funding

• NIH Clinical Center "Bench to Bedside" Award: Testing Neurobehavioral Endophenotypes of Loss of Control Eating, NICHD 2014–2015
• NICHD Division of Intramural Research Director's Investigator Award: Suppression of NLRP3 inflammasome activation to ameliorate obesity-associated metabolic abnormalities 2014–2015
• Office of Disease Prevention, NIH: Grant supplement to support the clinical protocol "Mood and Insulin Resistance in Adolescents at Risk for Diabetes" 2014-2015
• Zafgen Inc: Randomized, Double-Blind, Placebo Controlled, Phase 3 Trial of ZGN-440 (Subcutaneous Beloranib in Suspension, Zafgen, Inc.) in Obese Subjects with Prader-Willi Syndrome to Evaluate Total Body Weight, Food-related Behavior, and Safety over 6 Months. Funds an RCT testing a new methionine aminopeptidase inhibitor in patients with Prader-Willi Syndrome and obesity. 2014 – 2017

Publications

1. Hohenadel MG, Thearle MS, Grice BA, Huang H, Dai MH, Tao YX, Hunter LA, Palaguachi GI, Mou Z, Kim RC, Tsang MM, Haack K, Voruganti VS, Cole SA, Butte NF, Comuzzie AG, Muller YL, Baier LJ, Krakoff J, Knowler WC, Yanovski JA, Han JC. Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants. Int J Obes (Lond) 2014;2:56ra81.
2. Mou Z, Hyde TM, Lipska BK, Martinowich K, Wei P, Ong C, Hunter LA, Palaguachi GI, Morgun E, Teng R, Lai CF, Condarco TA, Demidowich AP, Krause AJ, Marshall LJ, Haack K, Voguganti S, Cole SA, Butte NF, Comuzzie AG, Nalls MA, Zonderman AB, Singleton AB, Evans MK, Martin B, Maudsley S, Tsao JW, Kleinman JE, Yanovski JA, Han JC. Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus. Cell Rep 2015; 13(6):1073-80.
3. Radin RM, Tanofsky-Kraff M, Shomaker LB, Kelly NR, Pickworth CK, Shank LM, Altschul AM, Brady SM, Demidowich AP, Yanovski SZ, Hubbard VS, Yanovski JA. Metabolic characteristics of youth with loss of control eating. Eat Behav 2015;19:86-89.
4. Adeyemo MA, McDuffie JR, Kozlosky M, Krakoff J, Calis KA, Brady SM, Yanovski JA. Effects of metformin on energy intake and satiety in obese children. Diabetes Obes Metab 2015;17:363-370.
5. Tanofsky-Kraff M, Shomaker LB, Wilfley DE, Young JF, Sbrocco T, Stephens M, Ranzenhofer LM, Elliott C, Brady S, Radin RM, Vannucci A, Bryant EJ, Osborn R, Berger SS, Olsen C, Kozlosky M, Reynolds JC, Yanovski JA. Targeted prevention of excess weight gain and eating disorders in high-risk adolescent girls: a randomized controlled trial. Am J Clin Nutr 2014;100:1010-1018.

Collaborators

• Silva Arslanian, MD, Children’s Hospital of Pittsburgh, Pittsburgh, PA
• Jeffrey Baron, MD, Program in Developmental Endocrinology and Genetics, NICHD, Bethesda, MD
• Andrew Butler, PhD, The Scripps Research Institute, La Jolla, CA
• Nancy Butte, PhD, Baylor College of Medicine, Houston, TX
• Samuel Cushman, PhD, Diabetes Branch, NIDDK, Bethesda, MD
• Kong Chen, PhD, Clinical Endocrinology Branch, NIDDK, Bethesda, MD
• Anthony Comuzzie, PhD, Southwest National Primate Research Center, San Antonio, Texas
• Katherine Flegal, MPH, PhD, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD
• I. Sadaf Farooqi, MD, Cambridge Institute for Medical Research, Cambridge, UK
• Oksana Gavrilova, PhD, Mouse Metabolism Core Laboratory, NIDDK, Bethesda, MD
• Joan C. Han, MD, Le Bonheur Children’s Hospital, Memphis, TN
• Steven B. Heymsfield, MD, Pennington Biomedical Research Center, Baton Rouge, LA
• Michael Jensen, MD, Mayo Clinic, Rochester, MN
• Rudolph L. Leibel, MD, Columbia University College of Physicians and Surgeons, New York, NY
• Sergey Leikin, PhD, Section on Physical Biochemistry, NICHD, Bethesda, MD
• David S. Ludwig, MD, PhD, Children’s Hospital, Boston, Boston, MA
• Stephen O’Rahilly, MD, Cambridge Institute for Medical Research, Cambridge, UK
• Dale A. Schoeller, PhD, University of Wisconsin, Madison, WI
• Lauren B. Shomaker, PhD, University of Colorado, Boulder, CO
• Eric Stice, PhD, Oregon Research Institute, Eugene, OR
• Marian Tanofsky-Kraff, PhD, Uniformed Services University of the Health Sciences, Bethesda, MD
• B. Timothy Walsh, PhD, Columbia University College of Physicians and Surgeons, New York, NY
• Denise E. Wilfley, PhD, Washington University School of Medicine, St. Louis, MO
• Heiner Westphal, MD, Program in Genomics of Differentiation, NICHD, Bethesda, MD
• Joshua Zimmerberg, MD, PhD, Program in Physical Biology, NICHD, Bethesda, MD

Contact

For more information, email yanovskj@mail.nih.gov or visit http://sgo.nichd.nih.gov.

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