Hypothalamic Protein Kinase C Regulates Glucose Production

  1. Rachel Ross1,
  2. Penny Y.T. Wang2,
  3. Madhu Chari23,
  4. Carol K.L. Lam23,
  5. Liora Caspi2,
  6. Hiraku Ono1,
  7. Evan D. Muse1,
  8. Xiaosong Li1,
  9. Roger Gutierrez-Juarez1,
  10. Peter E. Light4,
  11. Gary J. Schwartz1,
  12. Luciano Rossetti1 and
  13. Tony K.T. Lam23
  1. 1Departments of Molecular Pharmacology, Medicine, and Neuroscience, Albert Einstein College of Medicine, Bronx, New York
  2. 2Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
  3. 3Departments of Physiology and Medicine, University of Toronto, Toronto, Canada
  4. 4Department of Pharmacology, University of Alberta, Edmonton, Canada
  1. Corresponding author: Dr. Tony Lam, tony.lam{at}uhnres.utoronto.ca

Abstract

OBJECTIVE—A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K+ (KATP) channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of KATP 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 KATP channels and regulate glucose production in normal rodents, we first activated hypothalamic PKC in the absence or presence of KATP 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 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 KATP 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 28 May 2008.

  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted May 16, 2008.
    • Received February 13, 2008.
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  1. Diabetes vol. 57 no. 8 2061-2065
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