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J. Biol. Chem., Vol. 278, Issue 33, 30614-30623, August 15, 2003

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Peroxisome Proliferator-activated Receptor- Represses GLUT4 Promoter Activity in Primary Adipocytes, and Rosiglitazone Alleviates This Effect^*

Michal Armoni  , Natalia Kritz , Chava Harel , Fabiana Bar-Yoseph , Hui Chen ¶, Michael J. Quon ¶ and Eddy Karnieli 

From the Institute of Endocrinology, Diabetes, and Metabolism, Rambam Medical Center and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel and the ^¶NCCAM, National Institutes of Health, Bethesda, Maryland 20892-1632

The synthetic thiazolidinedione ligands of peroxisome proliferator-activated receptor- (PPAR) improve insulin sensitivity in type II diabetes and induce GLUT4 mRNA expression in fat and muscle. However, the molecular mechanisms involved are still unclear. We studied the regulatory effects of PPAR and its ligands on GLUT4 gene expression in primary rat adipocytes and CHO-K1 cells cotransfected with PPAR and the GLUT4 promoter reporter. PPAR1 and PPAR2 repressed the activity of the GLUT4 promoter in a dose-dependent manner. Whereas this repression was augmented by the natural ligand 15-prostaglandin J₂, it was completely alleviated by rosiglitazone (Rg). Ligand binding-defective mutants PPAR1-L468A/E471A and PPAR2-L496A/E499A retained the repression effect, which was unaffected by Rg, whereas the PPAR2-S112A mutant exhibited a 50% reduced capacity to repress GLUT4 promoter activity. The –66/+163 bp GLUT4 promoter region was sufficient to mediate PPAR inhibitory effects. The PPAR/retinoid X receptor- heterodimer directly bound to this region, whereas binding was abolished in the presence of Rg. Thus, we show that PPAR represses transcriptional activity of the GLUT4 promoter via direct and specific binding of PPAR/retinoid X receptor- to the GLUT4 promoter. This effect requires an intact Ser¹¹² phosphorylation site on PPAR and is completely alleviated by Rg, acting via its ligand-binding domain. These data suggest a novel mechanism by which Rg exerts its antidiabetic effects via detaching PPAR from the GLUT4 gene promoter, thus leading to increased GLUT4 expression and enhanced insulin sensitivity.

Received for publication, May 5, 2003 , and in revised form, May 29, 2003.

^* This work was supported in part by Grant 358/99-2 from the Israel Science Foundation of the Israel Academy of Science and Humanities and by grants from the General Apotropus Fund-Israel Ministry of Health and the L. R. Diamond Fund. 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.

To whom correspondence should be addressed: Unit of Molecular Endocrinology, Inst. of Endocrinology, Diabetes, and Metabolism, Rambam Medical Center, Haifa 31096, Israel. Tel.: 972-4-854-3514; Fax: 972-4-854-2746; E-mail: amichal{at}tx.technion.ac.il.

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