OBJECTIVE-A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K +(K ATP)channels inhibit hepatic glucose production. 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 central nervous system lipids to activate K ATP channels and regulate glucose production 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 hypotha-lamic PKC via direct hypothalamic delivery of PKC activator 1-oleoyl-2-acetyl-sn-glycerol(OAG)suppressed glucose production. Coadministration of hypothalamic PKC-δ inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-δ and lower glucose production. Furthermore, hypothalamic dominant-negative Kir6.2 expression or the delivery of the K ATP. channel blocker glibenclamide abolished the glucose production-lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower glucose production. CONCLUSIONS-These studies indicate that hypothalamic PKC activation is sufficient and necessary for lowering glucose production.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism