Physiology, Psychology, and Genetics of Obesity

We are conducting studies to understand how the melanocortin 3 receptor (MC3R) affects energy regulation. We previously found an MC3R haplotype that is associated with adiposity in children and adults. Children and adults who were homozygous variant for both C17A and G241A polymorphisms had significantly greater fat mass and higher plasma levels of insulin and leptin than unaffected or heterozygous children and ate more at laboratory test meals. In vitro studies subsequently found that signal transduction and protein expression were significantly lower for the double mutant MC3R. The transgenic ‘knock-in’ mice we made to replace murine Mc3r with wild-type human (MC3R^hWT/hWT) and double-mutant (C17A+G241A) human (MC3R^hDM/hDM) MC3R indicated that MC3R^hDM/hDM mice had greater weight and fat mass but reduced length and fat-free mass than MC3R^hWT/hWT. Interestingly, MC3R^hDM/hDM mice have greater feeding efficiency than MC3R^hWT/hWT. MC3R^hDM/hDM bone– and adipose tissue–derived mesenchymal stem cells (MSCs) differentiate into adipocytes that accumulate more triglyceride than MC3R^hWT/hWT MSCs. MC3R^hDM/hDM, thus impacting nutrient partitioning to generate increased adipose tissue. Our studies this year found that at least part of the reason for adipose tissue hypertrophy in MC3R^hDM/hDM mice is that they have impaired lipolysis, with reduced hormone-sensitive lipase (HSL) phosphorylation in response to beta-adrenergic stimulation (Figure 1). We also have substantial data indicating a novel role for the MC3R in the regulation of hepatic autophagy (Figure 2). Both full knockouts and MC3R^hDM/hDM mice show impaired autophagy flux, while specific ligands for MC3R can activate hepatic autophagy pathways. Using tissue-specific knockout- and reactivation models, we now plan to study the importance of leukocyte MC3R hepatic and adipose tissue MC3R for whole body homeostasis.

Figure 1. Studies of lipolysis in a human MC3R variant

The MC3R^hDM/hDM variant is associated with pediatric-onset obesity. In mice whose MC3R was replaced by human versions of the gene, we found that adipocytes from MC3R^hDM/hDM mice had (A) lower lipolysis than mice with the human common (wild-type) version of the human gene (MC3R^hWT/hWT); we found the same reduced lipolysis (B) in people with the MC3R^hDM/hDM variant. Compared with (C) MC3R^hWT/hWT mice, mice with MC3R^hDM/hDM (D) had much lower ability to phosphorylate a key enzyme for lipolysis, and did not associate HSL (red) with lipid droplets (green), so that much less yellow (co-localized) signal was found in MC3R^hDM/hDM mice.

Click image to enlarge.

Click image to enlarge.

Figure 1. Studies of lipolysis in a human MC3R variant

The MC3R^hDM/hDM variant is associated with pediatric-onset obesity. In mice whose MC3R was replaced by human versions of the gene, we found that adipocytes from MC3R^hDM/hDM mice had (A) lower lipolysis than mice with the human common (wild-type) version of the human gene (MC3R^hWT/hWT); we found the same reduced lipolysis (B) in people with the MC3R^hDM/hDM variant. Compared with (C) MC3R^hWT/hWT mice, mice with MC3R^hDM/hDM (D) had much lower ability to phosphorylate a key enzyme for lipolysis, and did not associate HSL (red) with lipid droplets (green), so that much less yellow (co-localized) signal was found in MC3R^hDM/hDM mice.

Figure 2. Hepatic recovery of Mc3r demonstrates the role of Mc3r in autophagy.

Mice with recovery of Mc3r only in the liver (Mc3r^TB/TB Alb-Cre⁺⁺, blue bars and circles) have improved body weight (A, B), fat mass (C, D), liver triglycerides (TG) (E), and hepatic autophagy (F) compared with complete Mc3r inactivation (Mc3r^TB/TB, black bars and circles). There is almost complete restoration of normal hepatic TG and autophagy markers compared with wild-type mice (BL/6, open bars and circles).

Click image to enlarge.

Click image to enlarge.

Figure 2. Hepatic recovery of Mc3r demonstrates the role of Mc3r in autophagy.

Mice with recovery of Mc3r only in the liver (Mc3r^TB/TB Alb-Cre⁺⁺, blue bars and circles) have improved body weight (A, B), fat mass (C, D), liver triglycerides (TG) (E), and hepatic autophagy (F) compared with complete Mc3r inactivation (Mc3r^TB/TB, black bars and circles). There is almost complete restoration of normal hepatic TG and autophagy markers compared with wild-type mice (BL/6, open bars and circles).

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 we 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 they led to recent explorations of other syndromes associated with obesity that may cause dysregulation of leptin signaling, including WAGR, Bardet-Biedl, Alström, and Smith-Magenis syndromes [Reference 1]. 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 emotional dysregulation, food reinforcement and food-related inhibitory control, attention biases towards high palatability foods, 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 found that certain eating patterns may predict future weight gain in children at risk for obesity: children reporting binge-eating behaviors, such as loss of control 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 lower subsequent satiety, may play a role in the greater weight gain found in binge-eating children. We demonstrated, among cohorts of lean and obese youth, that youth with LOC eating had higher serum leptin and are at significantly greater risk for worsening of components of the metabolic syndrome than those without LOC episodes, even after adjusting for adiposity and other relevant covariates. These data 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 previously found that binge-eating behaviors were linked to attentional biases for high-palatability foods. In 2024, we reported results of a pilot attention-retraining study using smartphones to deliver the intervention in the natural environment, which showed that, using magnetoencephalography to interrogate attention-relevant brain areas, the attention-retraining (AR) group had reduced initial engagement in brain areas associated with reward response and subsequent increased goal-directed attention and action control [Reference 2].

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 the development of the complications of obesity in youth. We also examine body composition, leptin concentration, metabolic rate, insulin sensitivity, glucose disposal, energy intake at buffet meals, energy expenditure, 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. Children are being followed longitudinally into adulthood. In our 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. 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, finding 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.

Figure 3. Loss of control (LOC) eating and metabolic complications in a longitudinal study

On average (±SE), children who engaged in binge eating at baseline had more visceral adipose tissue at the L_2-3 intervertebral space at follow-up than children who did not engage in binge eating at baseline, adjusting for sex, race, baseline age, baseline visceral adipose tissue at L_2-3, and time in study (P = 0.01). On average (±SE), children who engaged in binge eating at baseline had higher follow-up triglycerides than children who did not engage in binge eating at baseline, adjusting for sex, race, baseline age, body mass index (kg/m²), baseline triglycerides, and time in study (P = 0.02).

Click image to enlarge.

Click image to enlarge.

Figure 3. Loss of control (LOC) eating and metabolic complications in a longitudinal study

On average (±SE), children who engaged in binge eating at baseline had more visceral adipose tissue at the L_2-3 intervertebral space at follow-up than children who did not engage in binge eating at baseline, adjusting for sex, race, baseline age, baseline visceral adipose tissue at L_2-3, and time in study (P = 0.01). On average (±SE), children who engaged in binge eating at baseline had higher follow-up triglycerides than children who did not engage in binge eating at baseline, adjusting for sex, race, baseline age, body mass index (kg/m²), baseline triglycerides, and time in study (P = 0.02).

Given the rapid increase in the prevalence of obesity, the development of treatments for obesity in children and adults is urgently needed, and current pharmacologic approaches show marked efficacy in adults [Reference 4], but remain more limited in children. In several clinical protocols, we examined approaches for the prevention and treatment of excessive body weight. In 2024, we reported the efficacy of the glucagon-like peptide 1 agonist liraglutide in adolescents who continue to have obesity despite sleeve gastrectomy bariatric surgery, finding that the body mass index (BMI) decreased by 4.3% with liraglutide. Adolescents who had poor initial response to their surgical procedure (less than 20% BMI reduction at BMI nadir) had less weight loss with liraglutide. Fasting glucose and hemoglobin A1C concentrations fell significantly. No serious treatment-emergent adverse events were reported. We studied the effects of modulation of the leptin signaling pathway with the melanocortin agonist setmelanotide in patients with proximal signaling defects in patients with Bardet Biedl syndrome and Smith Magenis syndrome [Reference 1]. Most recently, we completed another study of specific pharmacotherapy for patients with Prader-Willi syndrome using diazoxide choline extended release (DCCR), first during a placebo-controlled period and then versus a contemporaneously collected untreated group [Reference 4]. DCCR administration resulted in significant improvements in hyperphagia scores and even greater improvements in those with more severe baseline hyperphagia. We saw significant improvements in aggression, anxiety, and compulsivity, and reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin and lean body mass; disease severity was significantly reduced, as assessed by clinician and caregiver. 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 associated with obesity and thus improve its complications. Adults with obesity and metabolic syndrome, but who did not have diabetes, were randomized to 0.6 mg colchicine or placebo capsules twice daily for three months. Compared with placebo, colchicine significantly reduced C-reactive protein and erythrocyte sedimentation rate (Figure 4). The significant changes in homeostatic-model assessment of insulin resistance (HOMA-IR), fasting insulin, and glucose effectiveness suggested metabolic improvements in the colchicine versus placebo group, although we found few differences in the stool microbiome of colchicine-treated participants [Reference 5]. We are now conducting a larger, adequately powered study to determine whether colchicine improves insulin resistance and other measures of metabolic health in at-risk individuals.

Figure 4. Effects of colchicine on inflammatory and metabolic measures

Metabolic and inflammatory changes after three months of study medication in participants randomized to colchicine (N=21) or placebo (N=19).

A. Insulin sensitivity (S_I).

B. Fasting glucose.

C. Fasting insulin.

D. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR).

E. High sensitivity C-reactive protein (hsCRP).

F. Erythrocyte sedimentation rate (ESR).

G. White blood cell count (WBC).

H. Neutrophil count.

I. Platelet count. Data are presented as mean ± SEM.

Click image to enlarge.

Click image to enlarge.

Figure 4. Effects of colchicine on inflammatory and metabolic measures

Metabolic and inflammatory changes after three months of study medication in participants randomized to colchicine (N=21) or placebo (N=19).

A. Insulin sensitivity (S_I).

B. Fasting glucose.

C. Fasting insulin.

D. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR).

E. High sensitivity C-reactive protein (hsCRP).

F. Erythrocyte sedimentation rate (ESR).

G. White blood cell count (WBC).

H. Neutrophil count.

I. Platelet count. Data are presented as mean ± SEM.