Hypothalamic PKC regulates Glucose Production

Abstract

Objective: A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive potassium (K_ATP) channels inhibit hepatic glucose production (GP). The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of K_ATP channels remain unknown.

Research Design And Methods: To examine whether hypothalamic protein kinase C (PKC) mediates the ability of CNS lipids to activate K_ATP channels and regulate GP in normal rodents, we first activated hypothalamic PKC in the absence or presence of K_ATP channel inhibition. We then inhibited hypothalamic PKC in the presence of lipids. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of hypothalamic administrations on glucose metabolism in vivo.

Results: We first reported that direct activation of hypothalamic PKC via direct hypothalamic delivery of PKC activator 1-Oleoyl-2-acetyl-sn-glycerol (OAG) suppressed GP. Co-administration of hypothalamic PKC-δ inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-δ and lower GP. Furthermore, hypothalamic dominant negative-Kir6.2 expression or the delivery of the K_ATP channel blocker glibenclamide abolished the GP lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower GP.

Conclusion: These studies indicate that hypothalamic PKC activation is sufficient and necessary to lower GP.