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

Abstract

PPARγ (peroxisome proliferator-activated receptor gamma) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Here, we report that PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced expression of PPARγ 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. PPARγ acetylation was also induced by pioglitazone and acetylation is required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating the Dio mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high fat diet induced–insulin resistance. Our data suggest that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for improvement of insulin sensitivity.

Thiazolidinediones and the Promise of Insulin Sensitization in Type 2 Diabetes

“…These authors propose a model whereby ligand-mediated PPARγ interaction with the deacetylase SirT1 results in deacetylation and alterations in the PPARγ gene activation profile favoring a beige adipocyte phenotype. Another recent study suggests a conflicting model based on an observation that pioglitazone instead increases acetylation of endogenous PPARγ in cultured adipocytes (Jiang et al, 2014). …”

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…Along the same line, inhibition of HDAC3 activates PPARγ to improve insulin sensitivity in diet-induced obesity (Jiang et al, 2014). PPARγ activation by exogenous ligands including thiazolidinediones is commonly used in the therapeutics of type 2 diabetes mellitus to enhance insulin sensitivity.…”

“…This is supported by enhanced expression of PPARγ target genes such as adiponectin and aP2, leading to an increase in glucose uptake and insulin signaling in adipocytes, as well as enhanced lipid accumulation during differentiation of adipocytes, following HDAC3 inhibition. Thus, in the absence of thiazolidinediones, acetylation from HDAC3 inhibition may induce the transcriptional activity of PPARγ (Jiang et al, 2014).…”

Histone Deacetylases and Cardiometabolic Diseases

“…Conversely, thermogenic beige and brown adipocytes promote insulin sensitivity and weight loss 22 . HDAC3 inhibition was reported to regulate PPARγ acetylation and activity, thereby enhancing insulin signaling and glucose uptake in white adipocytes and improving insulin sensitivity in diet-induced obese (DIO) mice 23 . Adipose HDAC3 was also demonstrated to repress phosphoenolpyruvate carboxykinase, the key enzyme controlling glyceroneogenesis, resulting in reduced triglyceride biosynthesis and lipodystrophy.…”