Role of brainstem melanocortin-4 receptor (MC4R) in regulating glucose, energy balance and body fat in female mice (Abstract only)

The central melanocortin system, particularly the melanocortin-4 receptor (MC4R), plays an important role in regulation of energy homeostasis. Although the brainstem has a high density of MC4R, their role in regulating metabolic functions, including energy balance, glucose, and body weight has not been fully elucidated. Using Cre-LoxP technology, we selectively rescued MC4R in preganglionic parasympathetic neurons of the nucleus tractus solitaries/dorsal motor nucleus of the vagus nerve (NTS/DMV) of female mice with whole body MC4R deficiency (Phox2b/LoxTB-MC4R−/−, n=7). Littermate MC4R-deficient mice (LoxTB-MC4R−/−, n=7) were used as controls. Body weight, body composition, and glucose tolerance were determined at 20 weeks of age. At 19–22 weeks of age, the mice were placed in metabolic cages for measurement of daily food intake, oxygen consumption (VO2), heat production, and locomotor activity (MA). Compared to LoxTB-MC4R−/− mice, Phox2b/LoxT-MC4R−/− were less obese (38±3 vs. 47±1g) with decreased food intake (2.8±0.5 vs. 4.5±0.2 g), increased VO2 (65.5±2.9 vs. 60.0±0.4 mL·kg−1·min−1) and MA (306±49 vs. 99±6 cm·hr−1), and similar heat production (832±22 vs. 835±54 cal·hr−1). Phox2b/LoxTB-MC4R−/− mice exhibited similar body fat percentage (45±1 vs. 46±2%) at 20 weeks of age compared to LoxTB-MC4R−/−. Blood glucose levels and tolerance to a glucose load were similar (140±7 vs.138±13 mg·dL−1; AUC: 25866±2069 vs. 25097±4677 mg·min·dL−1) in Phox2b/LoxT-MC4R−/− compared to LoxTB-MC4R−/− mice. Rescuing MC4R in preganglionic parasympathetic neurons in the brainstem did not restore the anorexic (2.8±0.5 vs. 2.9±0.4 g) or the glucose lowering effects of leptin (125 ±32 to 121 ±30.5 mg·dL−1). These results suggest that MC4R activity in the brainstem, specifically in the NTS/DMV, contributes to regulation of appetite, body weight, energy expenditure, and locomotor activity in female mice. We did not observe a major role for MC4R in NTS/DMV in controlling fasting glucose, glucose tolerance, body fat percentage, or rescuing the anorexic and anti-diabetic effects of leptin.