Glucagon Action in the Dorsal Vagal Complex and the Regulation of Glucose Homeostasis during High-protein Feeding

High-protein feeding acutely lowers plasma glucose compared to low-protein feeding, despite a seemingly dichotomous stimulation of circulating glucagon concentration. The physiological function of this postprandial glucagon rise has been largely overlooked. Notably, glucagon has recently been discovered to trigger a negative-feedback system in the brain to reduce glucose production. Here, we tested the hypothesis that glucagon signals in the dorsal vagal complex (DVC) to mediate the glucose-lowering effect of high-protein feeding. First, we found that intra-DVC administration of glucagon suppresses glucose production in vivo. Second, we identified a Gcgr–PKA–Erk1/2–KATP channel signalling mechanism of DVC glucagon action. Third, we demonstrated that disruption of Gcgr signalling in the DVC blunts the ability of high-protein feeding to acutely lower plasma glucose levels compared to low-protein feeding. Collectively, these data revise the traditional view of how high-protein feeding regulates glucose homeostasis and introduce a physiological role of postprandial brain glucagon action.M.Sc.2016-11-26 00:00:0