Hypothalamic protein kinase C regulates glucose production

Rachel Ross, Penny Y.T. Wang, Madhu Chari, Carol K.L. Lam, Liora Caspi, Hiraku Ono, Evan D. Muse, Xiaosong Li, Roger Gutierrez-Juarez, Peter E. Light, Gary J. Schwartz, Luciano Rossetti, Tony K.T. Lam

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2061-2065
Number of pages5
JournalDiabetes
Volume57
Issue number8
DOIs
Publication statusPublished - Aug 1 2008

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ross, R., Wang, P. Y. T., Chari, M., Lam, C. K. L., Caspi, L., Ono, H., ... Lam, T. K. T. (2008). Hypothalamic protein kinase C regulates glucose production. Diabetes, 57(8), 2061-2065. https://doi.org/10.2337/db08-0206