The peroxisome proliferator-activated receptor-␥ (PPAR␥, 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␥/ 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␥1 and -␥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␥, whereas PARP-2 overexpression enhances the basal activity of PPAR␥, although it does not change the maximal ligand-dependent activation. In addition, we show a DNA-dependent interaction of PARP-2 and PPAR␥/RXR heterodimer by chromatin immunoprecipitation. In combination, our results suggest that PARP-2 is a novel cofactor of PPAR␥ activity.Adipose tissue is composed of adipocytes that store energy in the form of triglycerides. Excessive accumulation of white adipose tissue (WAT) 2 leads to obesity, whereas its absence leads to lipodystrophic syndromes. The peroxisome proliferatoractivated receptor-␥ (PPAR␥, NR1C3) is the main protein orchestrating the differentiation and function of WAT, as evidenced by the combination of in vitro studies, the analysis of mouse models, and the characterization of patients with mutations in the human PPAR␥ gene (1, 2). PPAR␥ acts as heterodimer with the retinoid X receptor (RXR) (3). The PPAR␥/RXR receptor dimer is involved in the transcriptional control of energy, lipid, and glucose homeostasis (4, 5). The actions of PPAR␥ are mediated by two protein isoforms, the widely expressed PPAR␥ 1 and adipose tissue-restricted PPAR␥ 2 , both produced from a single gene by alternative splicing and differing only by an additional 28 amino acids in the N terminus of PPAR␥ 2 (3, 6).PPAR␥ is activated by binding of small lipophilic ligands, mainly fatty acids, derived from nutrition or metabolic pathways, or synthetic agonists, like the anti-diabetic thiazolidenediones (2,7,8). Docking of these ligands in the ligand binding pocket alters the conformation of PPAR␥, resulting in transcriptional activation subsequent to the release of corepressors and the recruitment of coactivators. Many corepressors and coactivators have been described such as the nuclear receptor corepressor and the steroid receptor coactivators, also known as p160 proteins (9 -11). These corepressors and coactivators determine transcriptional activity by altering chromatin structure via enzyme such as histone deacetylases and histone acetyltransferases (CREB-binding protein/p300). Other mechanisms include DNA methylation, ATP-dependent ...