TAZ Is a Negative Regulator of PPARγ Activity in Adipocytes and TAZ Deletion Improves Insulin Sensitivity and Glucose Tolerance

Insulin resistance is a major factor in obesity-linked type 2 diabetes. PPAR gamma is a master regulator of adipogenesis, and small molecule agonists, termed thiazolidinediones, are potent therapeutic insulin sensitizers. Here, we studied the role of transcriptional co-activator with PDZ-binding motif (TAZ) as a transcriptional co-repressor of PPAR gamma. We found that adipocyte-specific TAZ knockout (TAZ AKO) mice demonstrate a constitutively active PPAR gamma state. Obese TAZ AKO mice show improved glucose tolerance and insulin sensitivity compared to littermate controls. PPAR gamma response genes are upregulated in adipose tissue from TAZ AKO mice and adipose tissue inflammation was also decreased. In vitro and in vivo mechanistic studies revealed that the TAZ-PPAR gamma interaction is partially dependent on ERK-mediated Ser112 PPAR gamma phosphorylation. As adipocyte PPAR gamma Ser112 phosphorylation is increased in obesity, repression of PPAR gamma activity by TAZ could contribute to insulin resistance. These results identify TAZ as a new factor in the development of obesity-induced insulin resistance.