Postprandial glucose sensing by POMC neurons regulates appetite and energy metabolism (#121)
Monogenic mutations in neural anorectic pathways controlling appetite produce severe human obesity. One such neural population is the POMC population in the arcuate nucleus of the hypothalamus. Under long-term chronic conditions POMC neurons maintain energy balance by regulating appetite, glucose homeostasis and energy expenditure. Although POMC neurons sense glucose to control glucose homeostasis, is remains unknown whether POMC neurons sense meal-to-meal changes in glucose to control acute food intake and energy expenditure. In this study, we employed a fasted/refeeding paradigm, as refeeding significantly increases blood glucose, to examine if post-prandial glucose-sensing controls appetite and body weight. Initial experiments show that POMC neurons are activated acutely within 30 minutes of refeeding, an effect that persists for 2 hours. In order to examine POMC neuron glucose-sensing we developed a POMC specific deletion of carnitine acetyltransferase (Crat). Crat is a mitochondrial enzyme facilitates glucose breakdown via glycolysis. Deletion of Crat in POMC neurons increased food intake compared to controls after refeeding and oral glucose gavage and also reduced POMC neuronal activation in the hypothalamus as assessed by PCR and cfos immunohistohistochemisty. Finally, exposure to high fat diet for 10 weeks also increased body weight, food intake and glucose intolerance POMC crat knockout compared to wild type controls. Our results indicate that glucose-sensing by Crat in POMC neurons controls acute food intake and hypothalamic POMC neuronal function. Furthermore, we suggest in the long term this predisposes to body weight gain and glucose intolerance. These results implicate dysfunctional POMC glucose-sensing in the pathogenesis of obesity and diabetes.