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J. Biol. Chem., Vol. 281, Issue 12, 7960-7967, March 24, 2006

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Activation of CCAAT/Enhancer-binding Protein (C/EBP) Expression by C/EBP during Adipogenesis Requires a Peroxisome Proliferator-activated Receptor--associated Repression of HDAC1 at the C/ebp Gene Promoter^*

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

Studies have shown that CCAAT/enhancer-binding protein (C/EBP) can stimulate adipogenesis in noncommitted fibroblasts by activating expression of peroxisome proliferator-activated receptor- (PPAR). Other investigations have established a role for C/EBP as well as PPAR in orchestrating the complex program of adipogenic gene expression during terminal preadipocyte differentiation. Consequently, it is important to identify factors regulating transcription of the C/ebp gene. In this study, we demonstrated that inhibition of PPAR activity by exposure of 3T3-L1 preadipocytes to a potent and selective PPAR antagonist inhibits adipogenesis but also blocks the activation of C/EBP expression at the onset of differentiation. Ectopic expression of C/EBP in Swiss 3T3 mouse fibroblasts (Swiss-LAP cells) induces PPAR expression without any significant enhancement of C/EBP expression. Treatment of Swiss-LAP cells with a PPAR agonist induces adipogenesis, which includes activation of C/EBP expression. To further establish a role for PPAR in regulating C/EBP expression, we expressed C/EBP in PPAR-deficient mouse embryo fibroblasts (MEFs). The data show that C/EBP is capable of inducing PPAR in Ppar+/- MEFs, which leads to activation of adipogenesis, including C/EBP expression following exposure to a PPAR ligand. In contrast, C/EBP is not able to induce C/EBP expression or adipogenesis in Ppar-/- MEFs. Chromatin immunoprecipitation analysis reveals that C/EBP is bound to the minimal promoter of the C/ebp gene in association with HDAC1 in unstimulated Swiss-LAP cells. Exposure of the cells to a PPAR ligand dislodges HDAC1 from the proximal promoter of the C/ebp gene, which involves degradation of HDAC1 in the 26 S proteasome. These data suggest that C/EBP activates a single unified pathway of adipogenesis involving its stimulation of PPAR expression, which then activates C/EBP expression by dislodging HDAC1 from the promoter for degradation in the proteasome.

Received for publication, September 30, 2005 , and in revised form, December 12, 2005.

^* This work was supported by United States 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.

¹ 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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