Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation is dependent on a ligand. PPAR gamma activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes mellitus for the improvement of insulin sensitivity. In addition to a ligand, PPAR gamma function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Herein, we report that the PPAR gamma protein is modified by acetylation, which induces the PPAR gamma function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPAR gamma to deacetylate the protein. In immunoprecipitation assays, the HDAC3 protein was associated with the PPAR gamma protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPAR gamma protein. Furthermore, inhibition of HDAC3 enhanced the expression of PPAR gamma target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPAR gamma acetylation was also induced by pioglitazone and acetylation was required for PPAR gamma activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPAR gamma. Treating diet-induced obesity mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high-fat-diet-induced insulin resistance. Our results indicate that acetylation of PPAR gamma is a ligand-independent mechanism of PPAR gamma activation. HDAC3 inhibitor is a potential PPAR gamma activator for the improvement of insulin sensitivity.