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J. Biol. Chem., Vol. 280, Issue 46, 38317-38327, November 18, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/46/38317    most recent M505853200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, X. Articles by Burant, C. F. Search for Related Content PubMed PubMed Citation Articles by Li, X. Articles by Burant, C. F. Social Bookmarking                      What's this?

Distinct Mechanisms of Glucose Lowering by Specific Agonists for Peroxisomal Proliferator Activated Receptor and Retinoic Acid X Receptors^*

Xiangquan Li, Polly A. Hansen, Li Xi¶, Roshantha A. S. Chandraratna||, and Charles F. Burant1

From the Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, the Department of Biochemistry and Cell Biology,St. Louis University, St. Louis, Missouri 63104, ^¶Pfizer Global Research and Development, Ann Arbor, Michigan 48105, and ^||Retinoid Research, Vitae Pharmaceuticals, Irvine, California 92612

Agonists for the nuclear receptor peroxisomal proliferator-activated receptor- (PPAR) and its heterodimeric partner, retinoid X receptor (RXR), are effective agents for the treatment of type 2 diabetes. To gain insight into the antidiabetic action of these compounds, we treated female Zucker diabetic rats (ZFF) with AGN194204, which we show to be a homodimer-specific RXR agonist, or the PPAR agonist, troglitazone. Hyperinsulinemic-euglycemic clamps in ZFF showed that troglitazone and AGN194204 reduced basal endogenous glucose production (EGP) 30% and doubled the insulin suppression of EGP. AGN194204 had no effect on peripheral glucose utilization, whereas troglitazone increased insulin-stimulated glucose utilization by 50%, glucose uptake into skeletal muscle by 85%, and de novo skeletal muscle glycogen synthesis by 300%. Troglitazone increased skeletal muscle Irs-1 and phospho-Akt levels following in vivo insulin treatment, whereas AGN194204 increased hepatic Irs-2 and insulin stimulated phospho-Akt in liver. Gene profiles of AGN194204-treated mouse liver analyzed by Ingenuity Pathway Analysis identified increases in fatty acid synthetic genes, including Srebp-1 and fatty acid synthase, a pathway previously shown to be induced by RXR agonists. A network of down-regulated genes containing Foxa2, Foxa3, and G-protein subunits was identified, and decreases in these mRNA levels were confirmed by quantitative reverse transcription-PCR. Treatment of HepG2 cells with AGN194204 resulted in inhibition of glucagon-stimulated cAMP accumulation suggesting the G-protein down-regulation may provide an additional mechanism for hepatic insulin sensitization by RXR. These studies demonstrate distinct molecular events lead to insulin sensitization by high affinity RXR and PPAR agonists.

Received for publication, May 31, 2005 , and in revised form, September 16, 2005.

^* 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 Table S1.

¹ To whom correspondence should be addressed: Dept. of Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0354. Tel.: 734-615-3481; Fax: 734-936-6684; E-mail: burantc{at}umich.edu.

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