Inhibition of Histone Deacetylase Activity by Valproic Acid Blocks Adipogenesis

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