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J. Biol. Chem., Vol. 282, Issue 12, 8557-8567, March 23, 2007

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Activation of Lipoprotein Lipase by Glucose-dependent Insulinotropic Polypeptide in Adipocytes

A ROLE FOR A PROTEIN KINASE B, LKB1, AND AMP-ACTIVATED PROTEIN KINASE CASCADE^*

From the Department of Cellular and Physiological Sciences, the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Glucose-dependent insulinotropic polypeptide (GIP) has been mainly studied because of its glucose-dependent insulinotropic action and its ability to regulate -cell proliferation and survival. Considerably less is known about the effects of GIP on fat metabolism, and the present study was directed at identifying the mechanisms underlying its stimulatory action on lipoprotein lipase (LPL). In differentiated 3T3-L1 adipocytes, GIP, in the presence of insulin, increased LPL activity and triglyceride accumulation through a pathway involving increased phosphorylation of protein kinase B (PKB) and reductions in phosphorylated LKB1 and AMP-activated protein kinase (AMPK). Knockdown of AMPK using RNA interference and application of the AMPK inhibitor, Compound C, supported this conclusion. In contrast, the other major incretin hormone, glucagon-like peptide-1, exhibited no significant effects on LPL activity or PKB, LKB1, or AMPK phosphorylation. Cultured subcutaneous human adipocytes showed similar responses to GIP but with greater sensitivity. Chronic elevation of circulating GIP levels in the Vancouver diabetic fatty Zucker rat in vivo resulted in increased LPL activity and elevated triglyceride accumulation in epidydimal fat tissue, combined with a modulation of PKB, LKB1, and AMPK phosphorylation similar to that observed in vitro. This appears to be the first demonstration of a GIP-stimulated signal transduction pathway involved in increasing fat storage in adipocytes.

Received for publication, September 26, 2006 , and in revised form, January 17, 2007.

^* This work was supported by Canadian Institutes of Health Research Grants 590007 and OOP-79783 (to C. H. S. M.) and the Canadian Foundation for Innovation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence and reprint requests should be addressed: Dept. of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. Tel.: 822-3088; Fax: 822-6048; E-mail: mcintoch{at}interchange.ubc.ca.

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