Inhibition of HDAC3 promotes ligand-independent PPARγactivation by protein acetylation

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor whose activation is dependent on a ligand. PPARγactivation 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, PPARγfunction is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Herein, we report that the PPARγprotein is modified by acetylation, which induces the PPARγfunction in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγto deacetylate the protein. In immunoprecipitation assays, the HDAC3 protein was associated with the PPARγprotein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγprotein. Furthermore, inhibition of HDAC3 enhanced the expression of PPARγtarget 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. PPARγacetylation was also induced by pioglitazone and acetylation was required for PPARγactivation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. 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 PPARγis a ligand-independent mechanism of PPARγactivation. HDAC3 inhibitor is a potential PPARγactivator for the improvement of insulin sensitivity.