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J. Biol. Chem., Vol. 279, Issue 41, 42453-42461, October 8, 2004

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The Forkhead Transcription Factor FoxC2 Inhibits White Adipocyte Differentiation^*

Kathryn E. Davis, Marthe Moldes, and Stephen R. Farmer

From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

In this study, we show that expression of FoxC2 blocks the capacity of 3T3-L1 preadipocytes to undergo adipogenesis in the presence of dexamethasone, isobutylmethylxanthine, and insulin. This block is characterized by an extensive decrease in the expression of proteins associated with the function of the mature fat cell, most notably C/EBP, adiponectin, perilipin, and the adipose-specific fatty acid-binding protein, FABP4/aP2. Since the expression of these proteins lies downstream of PPAR, we overexpressed PPAR in Swiss mouse fibroblasts to promote adipocyte differentiation. We show that FoxC2 blocks the ability of PPAR to induce adipogenic gene expression in response to exposure of the cells to dexamethasone, isobutylmethylxanthine, insulin, and a PPAR ligand. Interestingly, the expression of aP2 escapes the inhibitory action of FoxC2 under conditions that promote maximum PPAR activity. In contrast, FoxC2 inhibits the expression of C/EBP, perilipin, and adiponectin even in the presence of potent PPAR ligands. Finally, we show that FoxC2 does not affect the ability of PPAR to bind to or transactivate from a PPAR response element. These data suggest that FoxC2 blocks adipogenesis by inhibiting the capacity of PPAR to promote the expression of a subset of adipogenic genes.

Received for publication, February 27, 2004 , and in revised form, June 30, 2004.

^* This work was supported by U. S. Public Health Service Grants DK51586 and DK58825. 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: Dept. of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4186; Fax: 617-638-5339; E-mail: farmer{at}biochem.bumc.bu.edu.

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