Physiology, Psychology, and Genetics of Obesity

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications & trials

Abstract

Obesity continues to be a major issue among children in the United States (1, 2). We continue to examine genes involved in the leptin signaling pathway to identify gene variants impacting body composition, with the expectation that improved understanding might help the development of precision medicine approaches for obesity. We are currently intensively studying a variant MC3R that is associated with adiposity in children and which appears to have functional significance for MC3R signal transduction. Children and adults who are homozygous for two rare polymorphisms (Thr6Lys and Val81Ile) have significantly greater fat mass and leptin compared with wild type or heterozygous children. Ongoing studies attempt to understand the mechanisms by which these sequence alterations impact body weight. We have successfully bred and studied novel knock-in mice expressing the human wild type MC3R(hWT/hWT) and human double-mutant MC3R(hDM/hDM). MC3R(hDM/hDM) have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) mice did not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiated into adipocytes that accumulated more triglyceride than MC3R(hWT/hWT) MSCs. MC3R(hDM/hDM) impacted nutrient partitioning to generate increased adipose tissue that appeared metabolically healthy. These data confirmed the importance of MC3R signaling in human metabolism and suggested a previously-unrecognized role for the MC3R in adipose tissue development. Current studies are seeking to understand better the roles of MC3R in peripheral metabolism including studies of hepatic autophagy. We have obtained a floxed Mc3r mouse, which will allow us to study tissue-specific knockouts of Mc3r in hepatocytes, adipocytes, and other tissues. We have previously found that leptin is an important predictor of weight gain in children and identified children with hyperleptinemia and leptin receptor mutations. We have also found hyperleptinemia 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, Bardet-Biedl (3), PCSK1, Leptin Receptor deficiency, and other conditions (4). Current studies are directed at understanding additional genetic, physiological, and psychological factors that place children at-risk for undue weight gain (5-12), including humoral factors (5), alterations in energy balance (6-9), food cravings (10), cognitive function (11), negative affective states and disinhibited eating (12). For example, over a mean follow-up from baseline of 8.5 years, adjusting for covariates and repeated measures of BMI or fat mass, linear mixed models revealed that weight-based teasing was associated with greater gain of BMI and fat mass across the follow-up period (ps .007). Adjusting for covariates, youths reporting high weight-based teasing (two standard deviations above the mean) experienced a 33% greater gain per year in BMI and a 91% greater gain in fat mass per year compared with peers who reported no weight-based teasing. Another series of pilot studies has tested if short bouts of activity may improve glucose tolerance or alter mood in children. In children who have normal weight or overweight, we found that interrupting sitting resulted in a significantly lower insulin and C-peptide Area vs continuous sitting during oral glucose tolerance test. Interrupting sedentary time with brief moderate-intensity walking thus improved short-term metabolic function. A new, recently completed trial tested if these acute improvements are sustained over 1 week, finding similar results. These studies may help lead to community studies examining if interrupting sedentary behavior is a promising prevention strategy for reducing cardiometabolic risk in children. Investigations concentrating on binge eating behaviors in children suggest that such behaviors are also associated with adiposity in children and predict future weight gain in children at-risk for overweight. Two completed protocols examined efficacy of interpersonal therapy (IPT) as a weight gain preventive strategy among children and adolescents who report binge eating behaviors versus a control health education (HE) program. Among girls with high self-reported baseline social-adjustment problems or anxiety, IPT, compared to HE, was associated with the steepest declines in BMIz (p<.001) and fat mass (p<=.03). Thus, in obesity-prone adolescent girls, IPT was associated with improvements in BMIz over 3 years among youth with high social-adjustment problems or trait anxiety. Youth with remission of Loss of Control (LOC) eating at end-of-treatment had lower serum glucose, higher high-density lipoprotein cholesterol and lower triglycerides at 6-month follow-up when compared with youth with persistent LOC. Thus, reducing LOC eating in adolescent girls may have a beneficial impact on some components of the metabolic syndrome. A new study is underway to examine if retraining attentional biases away from palatable foods can help children avoid weight gain. Given the rapid increase in the prevalence of obesity (1,2), the development of treatments for obesity is urgently needed. We have conducted translational trials related to modulation of the leptin signaling pathway using the melanocortin agonist called setmelanotide. Our data suggest that the leptin resistance of patients with the rare obesity-causing disorder Bardet Biedl syndrome is treatable with setmelanotide (3), which was recentl approved for use in this condition by the Food and Drug Administration. We have also completed a new randomized controlled study examining the use of diazoxide choline-controlled-release for the obesity of people with the Prader-Willi syndrome. Preliminary data suggest efficacy for those with significant hyperphagia. Finally, we have conducted studies to examine the hypothesis that administration of colchicine can decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation (13). 40 Adults with obesity were randomized to colchicine 0.6 mg or placebo capsules twice daily for 3 months. Compared with placebo, colchicine significantly reduced C-reactive protein (P <0.005), erythrocyte sedimentation rate (P <0.01), white blood cell count (P <0.005), and absolute neutrophil count (P <0.001). Changes in homeostatic model assessment of insulin resistance (P = 0.0499), fasting insulin (P = 0.07) and glucose effectiveness (P = 0.08), suggested metabolic improvements in the colchicine versus placebo group. This pilot study found colchicine significantly improved obesity-associated inflammatory variables among adults with obesity using a metabolomics approach (13). These results suggest a larger, adequately powered study should be conducted to determine whether colchicine improves insulin resistance and other measures of metabolic health in at-risk individuals. A trial for this purpose is underway. Additional collaborative studies (14-17), include a randomized controlled trial of a glucagon-like peptide-1 receptor agonist in people with hypothalamic obesity that suggests some individuals with this condition can be successfully treated with a GLP1 receptor agonist. We recently initiated a pilot study of a GLP1 receptor agonist in adolescents who have undergone sleeve gastrectomy but have insufficient weight loss.