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Originally published In Press as doi:10.1074/jbc.M304664200 on June 23, 2003

J. Biol. Chem., Vol. 278, Issue 39, 37672-37680, September 26, 2003
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The Orphan Nuclear Receptor Rev-Erb{alpha} Is a Peroxisome Proliferator-activated Receptor (PPAR) {gamma} Target Gene and Promotes PPAR{gamma}-induced Adipocyte Differentiation*

Coralie Fontaine {ddagger} §, Guillaume Dubois {ddagger} §, Yannick Duguay {ddagger} §, Torben Helledie ¶, Ngoc Vu-Dac {ddagger}, Philippe Gervois {ddagger}, Fabrice Soncin ||, Susanne Mandrup ¶, Jean-Charles Fruchart {ddagger}, Jamila Fruchart-Najib {ddagger} and Bart Staels {ddagger} **

From the {ddagger}UR545 INSERM, Département d'Athérosclérose, 1, rue Calmette, Institut Pasteur de Lille, 59019 Lille, France, and Faculté de Pharmacie, Université de Lille II, 59006 Lille, France, the ||Institut de Biologie de Lille, 1 rue Calmette, 59021 Lille, France, and the Department of Biochemistry and Molecular Biology, University of Southern Odense 5230, Denmark

Rev-Erb{alpha} (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor {alpha} gene. Rev-Erb{alpha} mRNA is induced during adipocyte differentiation of 3T3-L1 cells, and its expression is abundant in rat adipose tissue. Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) (NR1C3) is a nuclear receptor controlling adipocyte differentiation and insulin sensitivity. Here we show that Rev-Erb{alpha} expression is induced by PPAR{gamma} activation with rosiglitazone in rat epididymal and perirenal adipose tissues in vivo as well as in 3T3-L1 adipocytes in vitro. Furthermore, activated PPAR{gamma} induces Rev-Erb{alpha} promoter activity by binding to the direct repeat (DR)-2 response element Rev-DR2. Mutations of the 5' or 3' half-sites of the response element totally abrogated PPAR{gamma} binding and transcriptional activation, identifying this site as a novel type of functional PPAR{gamma} response element. Finally, ectopic expression of Rev-Erb{alpha} in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPAR{gamma} ligand rosiglitazone. These results identify Rev-Erb{alpha} as a target gene of PPAR{gamma} in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation.


Received for publication, May 5, 2003

* This work was supported by grants from Fonds Européens de Développement Régional, Conseil Régional Région Nord/Pas-de-Calais Genopole Project 01360124 and grants from the Leducq 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.

§ These authors contributed equally to this work.

** To whom correspondence should be addressed: UR545 INSERM, Département d'Athérosclérose, Institut Pasteur, 1 rue Calmette, 59019 Lille, France. Tel.: 33-3-20-87-73-88; Fax: 33-3-20-87-71-98; E-mail: Bart.Staels{at}pasteur-lille.fr.


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