Peroxisome proliferator-activated receptor (PPAR)-2 controls adipocyte differentiation and adipose tissue function through the regulation of the activity of the retinoid x receptor/PPARγ heterodimer

The peroxisome proliferator-activated receptor-gamma (PPAR gamma, NR1C3) in complex with the retinoid X receptor (RXR) plays a central role in white adipose tissue (WAT) differentiation and function, regulating the expression of key WAT proteins. In this report we show that poly(ADP-ribose) polymerase-2 (PARP-2), also known as an enzyme participating in the surveillance of the genome integrity, is a member of the PPAR gamma/ RXR transcription machinery. PARP-2(-/)-mice accumulate less WAT, characterized by smaller adipocytes. In the WAT of PARP-2(-/-)mice the expression of a number of PPAR target genes is reduced despite the fact that PPAR gamma 1 and -gamma 2 are expressed at normal levels. Consistent with this, PARP-2(-/)-mouse embryonic fibroblasts fail to differentiate to adipocytes. In transient transfection assays, PARP-2 small interference RNA decreases basal activity and ligand-dependent activation of PPAR gamma, whereas PARP-2 overexpression enhances the basal activity of PPAR gamma, although it does not change the maximal ligand-dependent activation. In addition, we show a DNA-dependent interaction of PARP-2 and PPAR gamma/RXR heterodimer by chromatin immunoprecipitation. In combination, our results suggest that PARP-2 is a novel cofactor of PPAR gamma activity.