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Physiology, Psychology, and Genetics of Obesity

• Jack A. Yanovski, MD, PhD, Head, Section on Growth and Obesity
• Sheila M. Brady, RN, FNP, Nurse Practitioner
• Tusharkumar Patel, PhD, Visiting Fellow
• Diana Elizondo, PhD, Postdoctoral Fellow
• Robin Roberson, MS, Technician
• Megan Parker, MS, Graduate Student, Guest Researcher
• Nasreen Moursi, BA, Graduate Student, Guest Researcher
• Praise Adekola, BA, Postbaccalaureate Intramural Research Training Award Fellow
• Bess Bloomer, BA, Postbaccalaureate Intramural Research Training Award Fellow
• Jocelyn Chen, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Jack Donahue, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Melanie Hollis, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Jeremiah Jones, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Celine Kisimba, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Esther Kwarteng, BA, Postbaccalaureate Intramural Research Training Award Fellow
• Julia Lazareva, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Lucy Loch, BA, Postbaccalaureate Intramural Research Training Award Fellow
• Alexa P. Lyman, BS, Postbaccalaureate Intramural Research Training Award Fellow
• Ejike Nwosu, BA, Postbaccalaureate Intramural Research Training Award Fellow
• Jennifer Te-Vazquez, BA, Postbaccalaureate 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 energy-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 cohorts of children who have undergone intensive metabolic and behavioral phenotyping, we examine genetic and phenotypic factors predictive of progression to adult obesity in children who have obesity or are in the “pre-obese” state, permitting characterization of phenotypes unconfounded by the impact of obesity itself. Once they are identified as linked to obesity, we intensively study 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. Such genes include the leptin receptor (LEPR), genes that appear to alter leptin receptor signal transduction such as those that are part of the BBSome (a protein complex of seven proteins), and those encoding proopiomelanocortin (POMC), the melanocortin 3 receptor (MC3R), the melanocortin 4 receptor (MC4R), and the brain-derived neurotrophic factor (BDNF). We are currently studying a variant MC3R that is associated with adiposity in children and adults and appears to have functional significance for MC3R signal transduction. Children and adults 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 (DM) MC3R. Our ongoing studies attempt to understand the mechanisms by which these sequence alterations affect body weight. We therefore developed transgenic ‘knock-in’ mice expressing the human wild-type (WT) and the human DM MC3R. Using homozygous knock-in mouse models replacing murine Mc3r with WT human (MC3R^hWT/hWT) and DM (C17A+G241A) human (MC3R^hDM/hDM) MC3R, we found that MC3R^hDM/hDM mice have greater weight and fat mass (Figure 2), increased energy intake and feeding efficiency, but lower length and fat-free mass than MC3R^hWT/hWT. MC3R^hDM/hDM mice do not have increased adipose tissue inflammatory-cell infiltration or greater expression of inflammatory markers despite their greater fat mass. Serum adiponectin is elevated in MC3R^hDM/hDM mice and in MC3R^hDM/hDM human subjects (Figure 2). MC3R^hDM/hDM bone- and adipose tissue–derived mesenchymal stem cells (MSCs) differentiate into adipocytes that accumulate more triglyceride than do MC3R^hWT/hWT MSCs. MC3R^hDM/hDM thus impacts nutrient partitioning to generate increased adipose tissue that appears metabolically healthy. These data confirm the importance of MC3R signaling in human metabolism and suggest a previously unrecognized role for the MC3R in adipose tissue development. Ongoing studies continue to improve our understanding of the phenotype of such mice. We are investigating a novel role for MC3R in regulating hepatic autophagy, the role MC3R plays in stem-cell fate, and how variations in Mc3r may alter signaling of several downstream signaling pathways. Using tissue-specific knockout and reactivation models, we are also studying the importance of hepatic and adipose tissue MC3R for whole body homeostasis.

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 we studied the short- and long-term stability of the components of the metabolic syndrome. We previously found that leptin is an important predictor of weight gain in children and identified children with hyperleptinemia and proximal leptin-signaling pathway mutations. We also found hyperleptinemia to be out of proportion with body fat mass in children with psychological loss of control (LOC) over-eating. Such data suggest the importance of leptin resistance as a factor stimulating weight gain and have led to recent explorations of other syndromes associated with obesity that may cause dysregulation of leptin signaling, including WAGR (Wilms tumor-aniridia genitourinary anomalies and mental retardation), Bardet-Biedl, and Alström syndromes [Reference 1]. Our current studies are directed at understanding additional genetic, physiological, and psychological factors that place children at risk for undue weight gain, including humoral factors, sleep, negative affective states such as depression and anxiety, food reinforcement and food-related inhibitory control [Reference 2], alexithymia, executive functioning, and LOC eating. Some recent initiatives have targeted insulin resistance in girls at high risk for type 2 diabetes because of obesity and a family history of diabetes.

Our evaluations concentrating on binge-eating behaviors in children suggest that such behaviors are also associated with adiposity in children and abnormalities in metabolism. We have found that certain eating patterns may predict future weight gain in children at risk for obesity: children reporting binge-eating behaviors such as 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 reduced subsequent satiety, may play a role in the greater weight gain found in binge-eating children. Among cohorts of lean and obese youth, we demonstrated that youth with LOC eating have significantly higher serum leptin and are at significantly greater risk for worsening of components of the metabolic syndrome compared with those without LOC episodes, even after adjusting for adiposity and other relevant covariates. Our data also suggest that anxiety symptoms may interact with LOC eating to become an important co-factor for excessive weight gain among 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 trials of preventative strategies related to binge eating.

We study normal-weight children and adolescents, children who already have obesity, and the children of parents with obesity who do not have obesity, 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, energy expenditure [Reference 3], 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 3), and sleep are also studied. We are following children 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 also investigated the role of sedentary behaviors, such as television watching, as a factor that alters metabolism. In a randomized, controlled, crossover trial (Figure 4) and in a 5-day parallel groups design, we found that glucose homeostasis was markedly improved in children with overweight or obesity who engaged in moderate activity for just three minutes every half hour, versus remaining sedentary.

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. In several clinical protocols, we examined approaches for the prevention and treatment of excessive body weight. We completed a randomized controlled trial to examine 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. Compared with placebo-treated children, those randomized to metformin significantly decreased BMI, BMI-Z score, and body fat mass. Serum glucose and HOMA-IR (homeostasis model assessment of insulin resistance) also declined significantly more in metformin-treated than in placebo-treated children. A second study examined the prevention of weight gain using interpersonal therapy (IPT) versus a control health education program (HE) in adolescents reporting LOC eating behaviors. At three-year follow-up, baseline social-adjustment problems and trait-anxiety moderated outcome. Among girls with high self-reported baseline social-adjustment problems or anxiety, IPT was associated with the steepest declines in BMIz compared with HE. For adiposity, girls with high or low anxiety in HE and girls with low anxiety in IPT experienced gains, while girls in IPT with high anxiety stabilized. Parent reports yielded complementary findings. The results have stimulated ongoing research to examine how anxiety may stimulate energy intake. We also published preliminary data from a third study examining IPT approaches in younger children, finding good tolerability for such a program. A fourth study examined whether reducing depressive symptoms could ameliorate insulin resistance in adolescents at risk for type 2 Diabetes. Among girls with greater (moderate) baseline depressive symptoms, those in cognitive behavioral therapy (CBT) developed significantly lower two-hour insulin than those in HE. Additional metabolic benefits of CBT were seen for this subgroup in post hoc analyses of post-treatment to 1-year change. An ongoing study, based on lab data finding links between attentional biases to high-palatability foods in children with obesity, investigates whether adolescents’ attentional biases can be retrained. We also studied the effects of modulating the leptin signaling pathway with the melanocortin agonist setmelanotide in patients with proximal signaling defects (patients with Bardet Biedl syndrome) [Reference 1]. Most recently, we completed another study of specific pharmacotherapy for patients with Prader-Willi syndrome, using diazoxide choline extended release [Reference 4]. These latest trials are examples of precision medicine approaches to treat obesity. We also completed a novel randomized controlled pilot trial of colchicine to ameliorate the inflammation of obesity and thus improve its complications [Reference 5]. Adults with obesity and metabolic syndrome, but who did not have diabetes, were randomized to colchicine 0.6 mg or placebo capsules twice daily for three months. Compared with placebo, colchicine significantly reduced C-reactive protein and erythrocyte sedimentation rate (Figure 5). The significant changes in homeostatic model assessment of insulin resistance, fasting insulin, and glucose effectiveness suggested metabolic improvements in the colchicine compared with the placebo group. Our group is now conducting a larger, adequately powered study to determine whether colchicine improves insulin resistance and other measures of metabolic health in at-risk individuals.

Additional Funding

• Rhythm Pharmaceuticals, Inc.: Setmelanotide (RM-493; Rhythm Pharmaceuticals, Inc.) phase 2 open-label treatment trials in patients with rare genetic disorders of obesity. 2017–2022.
• Soleno Therapeutics, Inc. Grant support to fund an RCT testing diazoxide choline sustained release tablets in patients with Prader-Willi syndrome and hyperphagia. 2018–2022.
• NICHD Office of Education Fellows Recruitment Incentive Award. Funds postdoctoral fellowship for Diana Elizondo, PhD, 2022–2023.

Publications

1. Haqq A, Chung WK, Dollfus H, Haws R, Martos-Moreno GA, Poitou C, Yanovski JA, Mittleman RS, Yuan G, Forsythe E, Clément K, Argente J. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol 2022 10(12):859–868.
2. Loch LK, Tanofsky-Kraff M, Parker MN, Haynes HE, Te-Vazquez JA, Bloomer BF, Lazareva J, Moursi NA, Nwosu EA, Yang SB, Turner SA, Brady SM, Bowling AI, Chen KY, Yanovski JA. Associations of food reinforcement and food-related inhibitory control with adiposity and weight gain in children and adolescents. Physiol Behav 2023 266:114198.
3. Speakman JR, de Jong JMA, Sinha S, Westerterp KR, Yamada Y, Yanovski JA, Schoeller DA, Wong WW. Total daily energy expenditure has declined over the last 3 decades due to declining basal expenditure not reduced activity expenditure. Nat Metab 2023 5(4):579–588.
4. Miller JL, Gevers E, Bridges N, Yanovski JA, Salehi P, Obrynba KS, Felner EI, Bird LM, Shoemaker AH, Angulo M, Butler MG, Stevenson D, Abuzzahab J, Barrett T, Lah M, Littlejohn E, Matthew V, Cowen NM, Bhatnagar A. Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2023 108(7):1676–1685.
5. Patel TB, Levine JA, Elizondo DM, Arner BE, Jain A, Saxena A, Lopez-Ocasio M, Dagur PK, Famuyiwa O, Gupta S, Sarrafan-Chaharsoughi Z, Biancotto A, McCoy JP, Demidowich AP, Yanovski JA. Immunomodulatory effects of colchicine on peripheral blood mononuclear cell subpopulations in human obesity: data from a randomized controlled trial. Obesity (Silver Spring) 2023 31(2):466–478.

Collaborators

• David Allison, PhD, School of Public Health, Indiana University, Bloomington, IN
• Jeffrey Baron, MD, Section on Growth and Development, NICHD, Bethesda, MD
• Britni Belcher, PhD, MPH, Keck School of Medicine, University of Southern California, Los Angeles, CA
• Karen Berman, PhD, Section on Integrative Neuroimaging, NIMH, Bethesda, MD
• Kong Chen, PhD, Clinical Endocrinology Branch, NIDDK, Bethesda, MD
• Ross Crosby, PhD, Director of Biomedical Statistics, Neuropsychiatric Research Institute, Fargo, ND
• Andrew P. Demidowich, MD, Johns Hopkins University School of Medicine, Baltimore, MD
• Joel Elmquist, DVM, PhD, UT Southwestern Medical Center, Dallas, TX
• Scott Engel, PhD, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND
• I. Sadaf Farooqi, MD, Cambridge Institute for Medical Research, Cambridge, United Kingdom
• Oksana Gavrilova, PhD, Mouse Metabolism Core Laboratory, NIDDK, Bethesda, MD
• Joan C. Han, MD, Le Bonheur Children’s Hospital, Memphis, TN
• Robert Haws, MD, Marshfield Clinic Research Institute, Marshfield, WI
• Steven B. Heymsfield, MD, Pennington Biomedical Research Center, Baton Rouge, LA
• Heidi Kong, MD, MHSc, Cutaneous Microbiome and Inflammation Section, NIAMS, Bethesda, MD
• Sergey Leikin, PhD, Section on Physical Biochemistry, NICHD, Bethesda, MD
• Joan C. Marini, MD, PhD, Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, Bethesda, MD
• Cara Olsen, PhD, Uniformed Services University of the Health Sciences, Bethesda, MD
• Vipul Periwal, PhD, Laboratory of Biological Modeling, NIDDK, Bethesda, MD
• Daniel Pine, MD, Section on Development and Affective Neuroscience, NIMH, Bethesda, MD
• Douglas Rosing, MD, Cardiac Consultation Service, NHLBI, Bethesda, MD
• Peter J. Schmidt, MD, Section on Behavioral Endocrinology, NIMH, Bethesda, MD
• Dale A. Schoeller, PhD, University of Wisconsin, Madison, WI
• Lauren B. Shomaker, PhD, University of Colorado, Boulder, CO
• Steven J. Soldin, PhD, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD
• John Speakman, PhD, University of Aberdeen, Aberdeen, United Kingdom
• 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
• Joshua Zimmerberg, MD, PhD, Section on Integrative Biophysics, NICHD, Bethesda, MD

Contact

For more information, email yanovskj@mail.nih.gov or visit https://www.nichd.nih.gov/research/atNICHD/Investigators/yanovski.

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