The Role of Central Glucagon Signaling in the Regulation of Glucose Homeostasis

Circulating glucagon activates hepatic G-protein coupled receptors to stimulate cAMP-dependent protein kinase A (PKA) signaling and increase glucose production (GP). The elevation of GP, however, is not sustained even in the presence of a continuous intravenous (i.v.) glucagon infusion that maintains elevated plasma glucagon levels. We here report that direct infusion of glucagon into the mediobasal hypothalamus of normal rats surprisingly inhibited GP during a pancreatic clamp. The GP-lowering effect required the activation of the hypothalamic glucagon receptor-cAMP-PKA pathway, while activation of the hypothalamic cAMP-PKA signaling alone was sufficient to lower GP. In a non-clamp setting, inhibition of the MBH glucagon receptor or cAMP-PKA signaling enhanced the acute ability of an i.v. glucagon injection to increase plasma glucose levels and GP in rats. Thus, we unveil a novel function of glucagon in the MBH that inhibits glucose production and counteracts the direct hepatic stimulatory effect of circulating glucagon in rats.MAS