1527-P: G Protein G_sα Is Required for Normal Glucose Sensing in POMC Neurons

Proopiomelanocortin (POMC) neurons are glucose-sensing neurons in which increased ambient glucose concentrations lead to neuronal activation by a mechanism involving K_ATP channels. Since glucose sensing in pancreatic β-cells occurs by a similar mechanism and requires G protein G_sα/cAMP signaling, we hypothesized that G_sα may also be involved in glucose sensing in POMC neurons. To test this hypothesis, we generated mouse models with POMC neuron-specific G_sα deficiency (POMCGsKO) or expression of a constitutively activated G_sα (POMCGsR201C). Despite having normal body weight and composition, POMCGsKO mice were hyperglycemic, hypoinsulinemic, glucose intolerant, and had impaired insulin response to glucose loading in vivo. In contrast, POMCGsR201C mice showed increased fat mass but improved glucose tolerance and enhanced insulin response to i.p. glucose administration. This altered glucose homeostasis by G_sα deficiency or activation in POMC neurons was not due to an autonomous pancreatic β-cell defect as both POMCGsKO and POMCGsR201C mice displayed normal pancreatic islet size and number, unchanged β-cell mass and intact glucose-stimulated insulin secretion from isolated islets ex vivo compared to controls. Instead, POMCGsKO mice lacked glucose-stimulated POMC neuron activation as determined by induction of c-fos expression, while POMCGsR201C mice exhibited higher basal c-fos activity in POMC neurons. These results indicate that G_sα is required for normal glucose sensing in POMC neurons which provide feedback to pancreatic islets to maintain glucose homeostasis.