The nuclear receptor corepressors NCoR and SMRT decrease peroxisome proliferator-activated receptor γ transcriptional activity and repress 3T3-L1 adipogenesis

The peroxisome proliferator-activated receptor γ (PPARγ) is a central regulator of adipogenesis and recruits coactivator proteins in response to ligand. However, the role of another class of nuclear cofactors, the nuclear receptor corepressors, in modulating PPARγ transcriptional activity is less clear. Such corepressors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT). Our data suggest that PPARγ recruits SMRT and NCoR in the absence of ligand and that these corepressors are capable of down-regulating PPARγ-mediated transcriptional activity. The addition of the PPARγ ligand pioglitazone results in dissociation of the PPARγ-corepressor complex. To define the role of SMRT and NCoR in PPARγ action, 3T3-L1 cells deficient in SMRT or NCoR were generated by RNA interference. When these cells are exposed to differentiation media, they exhibit increased expression of adipocyte-specific genes and increased production of lipid droplets, as compared with control cells. These data suggest that the nuclear receptor corepressors decrease PPARγ transcriptional activity and repress the adipogenic program in 3T3-L1 cells.