Physiology, Psychology, and Genetics of Obesity

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications & trials

Abstract

Obesity and its associated comorbid conditions continue to be major issues among children in the United States. 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. We created 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) 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. We recently found that MC3R plays an important role in hepatic autophagy, that contributes to its effects on systemic adiposity (1,2) These data confirmed the importance of MC3R signaling in human metabolism. 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 associated with weight gain and have led to recent explorations of other syndromes accompanying obesity that may cause dysregulation of leptin signaling, including WAGR, Bardet-Biedl, PCSK1, Leptin Receptor deficiency, and other conditions such as Smith Magenis Syndrome (3). Current studies are directed at understanding additional genetic, physiological, and psychological factors that place children at-risk for undue weight gain (4-14), including humoral factors, alterations in energy balance (5-6), stool microbiome socioeconomic (7-9) and familial factors (4) cognitive fatigue (10), negative affective states (11), and disinhibited eating (12-14). For example, we identified specific subphenotypes among youth with obesity linked to incident hypertension (4), and that loss of control eating was linked to development of components of the metabolic syndrome (14), but found no impact of cognitive fatigue on energy intake (10). 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. 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. We recently completed a new pilot study examining if retraining attentional biases away from palatable foods (AR) can be done in adolescent girls with overweight or obesity. We found a small effect of condition on energy intake (EMM(control) = 1017 kcal, EMM(AR) = 1088 kcal, d = 0.29). Within the AR group, there was slightly blunted initial engagement in brain areas associated with reward response and subsequent increased goal-directed attention and action control. We thus found preliminary support for efficacy of an intensive smartphone-delivered AR program to alter neural correlates of attention processing in adolescent girls with overweight or obesity. Studies with larger sample sizes are needed to elucidate if AR trainings disrupt the link between food AB and eating behavior. Given the rapid increase in the prevalence of obesity and its association with metabolic complications, the development of treatments for obesity is urgently needed, both for non-syndromic obesity (16) and for genetic conditions causing hyperphagia (17-18). 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. Similar studies have not identified marked improvements in body weight in patients with Smith-Magenis Syndrome (3), implicating involvement of signaling molecules that work further downstream of leptin signaling, including brain-derived neurotrophic factor, as etiologic factors for the obesity of Smith-Magenis Syndrome. We have also completed a randomized controlled study examining the use of diazoxide choline-extended-release for the obesity of people with the Prader-Willi syndrome an open-label extension, and a randomized controlled medication withdrawal phase, with the data suggestive of efficacy for those with significant hyperphagia (19-20) that have led to this medication recently becoming FDA approved for the hyperphagia of Prader Willi Syndrome. Lastly, we completed a pilot study of a GLP1 receptor agonist in adolescents who have undergone sleeve gastrectomy but have insufficient weight loss (2), finding approximately 5% weight reductions in this group. Another recent initiative has led to the discovery of the role of Transglutaminase 2 (TGM2)-expressing macrophages to modulate adipose tissue inflammation (22). Using Tgm2 CRISPR silencing, we examined TGM2 modulation of inflammation in vitro within bone marrow-derived macrophages (BMMs), as well as in co-cultured eWAT stromal vascular fraction (SVF) cells. Tgm2 silencing in BMMs led to increased pro-inflammation, compared to control. In contrast, in vitro exposure of eWAT SVF to recombinant TGM2 increased anti-inflammatory IL-10 secretion. However, IL-10 was not induced by recombinant TGM2 in CD activated CD4 + T cells, or in HFD-derived SVF CD4 + T cells. In vivo Tgm2 silencing in CD11b+ cells in HFD mice resulted in pro-inflammation in eWAT and serum, and increased adiposity and insulin resistance, suggesting that TGM2 + ATMs possess an anti-inflammatory role in obesity that is insufficient to reverse obesity-induced inflammation. Other collaborative publications have taken advantage of our samples of healthy youths as controls (23-24).