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J. Biol. Chem., Vol. 281, Issue 29, 19881-19891, July 21, 2006

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FOXO1 Represses Peroxisome Proliferator-activated Receptor-1 and -2 Gene Promoters in Primary Adipocytes

A NOVEL PARADIGM TO INCREASE INSULIN SENSITIVITY^*

Michal Armoni¹, Chava Harel, Shiri Karni, Hui Chen, Fabiana Bar-Yoseph, Marel R. Ver, Michael J. Quon, and Eddy Karnieli

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

FOXO1 and peroxisome proliferator-activated receptor- (PPAR) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive GLUT4 gene and that PPAR2 detachment from the GLUT4 promoter upon thiazolidinedione binding up-regulates GLUT4 gene expression, thus increasing insulin sensitivity (Armoni, M., Kritz, N., Harel, C., Bar-Yoseph, F., Chen, H., Quon, M. J., and Karnieli, E. (2003) J. Biol. Chem. 278, 30614–30623). However, the mechanisms regulating PPAR gene transcription are largely unknown. We studied the effects of FOXO1 on human PPAR gene expression in primary rat adipocytes and found that both genes are endogenously expressed. FOXO1 coexpression dose-dependently repressed transcription from either the PPAR 1 or PPAR2 promoter reporter by 65%, whereas insulin (100 nM, 20–24 h) either partially or completely reversed this effect. Phosphorylation-defective FOXO1 mutants T24A, S256A, S319A, and T24A/S256A/S319A still repressed the PPAR1 promoter and partially lost their effects on the PPAR2 promoter in either basal or insulin-stimulated cells. Use of DNA binding-defective FOXO1 (H215R) indicated that this domain is crucial for FOXO1 repression of the PPAR2 (but not PPAR1) promoter. Progressive 5'-deletion and gel retardation analyses revealed that this repression involves direct and specific binding of FOXO1 to the PPAR2 promoter; chromatin immunoprecipitation analysis confirmed that this binding occurs in cellulo. We suggest a novel paradigm to increase insulin sensitivity in adipocytes in which FOXO1 repression of PPAR, the latter being a repressor of the GLUT4 promoter, consequently leads to GLUT4 derepression/up-regulation, thus enhancing cellular insulin sensitivity. The newly identified FOXO1-binding site on the PPAR2 promoter may serve as a therapeutic target for type 2 diabetes.

Received for publication, January 12, 2006 , and in revised form, April 11, 2006.

^* This work was supported in part by grants from the L. R. Diamond Fund, the Technion-Israel Institute of Technology Vice President for Research Fund, and D-Cure and the Russell Berrie Foundation. 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.

¹ To whom correspondence should be addressed: Unit of Molecular Endocrinology, Inst. of Endocrinology, Diabetes and Metabolism, Rambam Medical Center, P. O. Box 9602, 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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