Augmentation of PPAR gamma-TAZ interaction contributes to the anti-adipogenic activity of KR62980

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a ligand-activated transcription factor that plays a pivotal role in the modulation of gene expression involved in adipocyte differentiation and insulin sensitivity. It has been previously established that thiazolidinedione (TZD) PPAR gamma ligands such as rosiglitazone have potent anti-diabetic and adipogenic activities. A novel non-TZD ligand for PPAR gamma, KR62980 has recently been characterized to increase insulin sensitivity and to be weakly adipogenic in 3T3-L1 cells or anti-adipogenic in rosiglitazone-induced adipocyte differentiation. In this study, we have confirmed that KR62980 substantially suppresses rosiglitazone-induced adipocyte differentiation and attenuates adipogenic gene expression via an induced reduction in PPAR gamma activity. KR62980 increased the nuclear localization of TAZ, a PPAR gamma suppressor, and also enhanced the interaction between PPAR gamma and TAZ, thus resulting in the TAZ-mediated suppression of PPAR gamma activity. Furthermore, KR62980 failed to suppress PPAR gamma-mediated adipogenic gene expression and adipocyte differentiation in TAZ knockdown 3T3-L1 cells, thus indicating a TAZ-dependent suppressive activity of KR62980 on PPAR gamma-mediated function. These findings strongly suggest that the novel PPAR gamma ligand, KR62980, may prove to be beneficial to anti-adipogenic function through the suppression of PPAR gamma-mediated adipocyte differentiation by activating TAZ. (C) 2009 Elsevier Inc. All rights reserved.