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

Peroxisome proliferator-activated receptor γ (PPARγ) 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) PPARγ ligands such as rosiglitazone have potent anti-diabetic and adipogenic activities. A novel non-TZD ligand for PPARγ, 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 PPARγ activity. KR62980 increased the nuclear localization of TAZ, a PPARγ suppressor, and also enhanced the interaction between PPARγ and TAZ, thus resulting in the TAZ-mediated suppression of PPARγ activity. Furthermore, KR62980 failed to suppress PPARγ-mediated adipogenic gene expression and adipocyte differentiation in TAZ knockdown 3T3-L1 cells, thus indicating a TAZ-dependent suppressive activity of KR62980 on PPARγ-mediated function. These findings strongly suggest that the novel PPARγ ligand, KR62980, may prove to be beneficial to anti-adipogenic function through the suppression of PPARγ-mediated adipocyte differentiation by activating TAZ.