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J. Biol. Chem., Vol. 279, Issue 18, 18851-18860, April 30, 2004

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Inhibition of Histone Deacetylase Activity by Valproic Acid Blocks Adipogenesis^*

Diane C. Lagace and Mark W. Nachtigal

From the Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada

Adipogenesis is dependent on the sequential activation of transcription factors including the CCAAT/enhancer-binding proteins (C/EBP), peroxisome proliferator-activated receptor (PPAR), and steroid regulatory element-binding protein (SREBP). We show that the mood stabilizing drug valproic acid (VPA; 0.5–2 mM) inhibits mouse 3T3 L1 and human preadipocyte differentiation, likely through its histone deacetylase (HDAC) inhibitory properties. The HDAC inhibitor trichostatin A (TSA) also inhibited adipogenesis, whereas the VPA analog valpromide, which does not possess HDAC inhibitory effects, did not prevent adipogenesis. Acute or chronic VPA treatment inhibited differentiation yet did not affect mitotic clonal expansion. VPA (1 mM) inhibited PPAR induced differentiation but does not activate a PPAR reporter gene, suggesting that it is not a PPAR ligand. VPA or TSA treatment reduced mRNA and protein levels of PPAR and SREBP1a. TSA reduced C/EBP mRNA and protein levels, whereas VPA only produced a decrease in C/EBP protein expression. Overall our results highlight a role for HDAC activity in adipogenesis that can be blocked by treatment with VPA.

Received for publication, November 24, 2003 , and in revised form, February 18, 2004.

^* This work was supported by the Canadian Psychiatric Research 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.

Supported by a Canadian Institutes of Health Research Doctoral Award.

Research Scientist of the Canadian Cancer Society through an award from the National Cancer Institute of Canada. To whom correspondence should be addressed: Dept. of Pharmacology, 5850 College St., Dalhousie University, Halifax, NS B3H 1X5, Canada. Tel.: 902-494-6348; Fax: 902-494-1388; E-mail: Mark.Nachtigal{at}Dal.Ca.

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