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J. Biol. Chem., Vol. 280, Issue 29, 27466-27476, July 22, 2005

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The Peroxisome Proliferator-activated Receptor- Regulates Murine Pyruvate Carboxylase Gene Expression in Vivo and in Vitro^*

Sarawut Jitrapakdee, Marc Slawik¶, Gema Medina-Gomez, Mark Campbell, John C. Wallace||, Jaswinder K. Sethi, Stephen O'Rahilly, and Antonio J. Vidal-Puig

From the Cambridge Institute of Diabetes, Endocrinology, and Metabolism and the Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QR, United Kingdom and the ^||School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia

Pyruvate carboxylase (PC) plays a crucial role in various metabolic pathways, including gluconeogenesis, lipogenesis, and glucose-induced insulin secretion. Here we showed for the first time that the PC gene is transcriptionally regulated by peroxisome proliferator-activated receptor- (PPAR) in vitro and in vivo in white and brown adipose tissue. PC mRNA and protein are markedly increased during differentiation of 3T3-L1 cells and HIB-1B, in parallel with the expression of the adipogenic transcription factors, CCAAT-enhancer binding protein , PPAR1, and PPAR2. Tumor necrosis factor-, a cytokine that blocks differentiation of 3T3-L1 cells, suppressed PC expression. Co-transfection studies in 3T3-L1 preadipocytes or HEK293T cells with a 2.3-kb promoter fragment of mouse PC gene linked to a luciferase reporter construct and with plasmids overexpressing retinoid X receptor /PPAR1 or retinoid X receptor /PPAR2 showed a 6-8-fold increase above the basal promoter activity. Furthermore, treatment of these transfected cells with the PPAR agonist doubled the promoter activity. Mutation of the putative PPAR-response element-(-386/-374) of this 2.3-kb PC promoter fragment abolished the PPAR response. Gel shift and chromatin immunoprecipitation assays demonstrated that endogenous PPAR binds to this functional PPAR-response element of the PC promoter. Mice with targeted disruption of the PPAR2 gene displayed 50-60% reduction of PC mRNA and protein in white adipose tissue. Similarly, in brown adipose tissue of PPAR2-deficient mice subjected to cold exposure, PC mRNA was 40% lower than that of wild type mice. Impaired in vitro differentiation of white adipocytes of PPAR2 knock-out mice was also associated with a marked reduction of PC mRNA. Our findings identified PC as a PPAR-regulated gene and suggested a role for PPAR regulating intermediary metabolism.

Received for publication, April 8, 2005 , and in revised form, May 24, 2005.

^* This work was supported in part by a Wellcome Trust Integrative Physiology grant (to A. V. P. and S. O'R.), a Biotechnology and Biological Sciences Research Council David Phillips fellowship (to J. K. S.), and a Medical Research Council Career Establishment grant (to A. V. P.). 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.

^¶ Supported by a fellowship from the Fritz Thyssen Foundation, Germany.

Supported by a Royal Society International Fellowship, UK. Performed work while on sabbatical leave from the Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand. To whom correspondence should be addressed. Tel.: 662-201-5460; Fax: 662-354-7174; E-mail: scsji{at}mahidol.ac.th.

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