Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis

doi:10.1074/jbc.M312795200

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Papers In Press, published online ahead of print February 24, 2004
J. Biol. Chem, 10.1074/jbc.M312795200
Submitted on November 24, 2003
Revised on February 18, 2004
Accepted on February 24, 2004

Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis

Diane C. Lagace and Mark W. Nachtigal

Pharmacology, Dalhousie University, Halifax, NS B3H 1X5

Corresponding Author: Mark.Nachtigal{at}Dal.Ca

Adipogenesis is dependent on the sequential activation of transcription factors including the CCAAT/enhancer binding proteins (C/EBP), peroxisome proliferator-activated receptor gamma (PPAR $gamma$ ), 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 (VPM), 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 $gamma$ induced differentiation, but does not activate a PPAR $gamma$ reporter gene, suggesting it is not a PPAR $gamma$ ligand. VPA or TSA treatment reduced mRNA and protein levels of PPAR $gamma$ , SREBP1a. TSA reduced C/EBP $alpha$ mRNA and protein levels, whereas VPA only produced a decrease in C/EBP $alpha$ protein expression. Overall our results highlight a role for HDAC activity in adipogenesis that can be blocked by treatment with VPA.

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