Nuclear receptor corepressors and PPARgamma

Abstract

The nuclear receptor corepressors NCoR and SMRT repress gene transcription by recruiting a histone deacetylase complex. Their roles in PPARgamma action have been controversial. Recent evidence, however, suggests that NCoR and SMRT repress PPARgamma-mediated transcriptional activity on specific promoters in the adipocyte. In addition, by repressing PPARgamma action, these corepressors inhibit the ability of adipocyte differentiation to proceed. A further understanding of corepressor action in the adipocyte will provide insight into the balance of forces regulating adipogenesis, insulin sensitivity, and Type 2 diabetes mellitus.

Figure 1. Corepressors modulate PPARγ activity via distinct mechanisms

Nuclear receptor corepressors (CoRs) are recruited to PPARγ on a subset of PPARγ-responsive positively-regulated genes (a). On these genes, corepressors repress PPARγ activity in the absence of ligand. The presence of ligands such as TZDs causes release of corepressors and recruitment of coactivators (CoAs). On other genes (b), PPARγ does not recruit corepressors, and these genes are transcriptionally active even in the absence of ligand. Still other genes are negatively regulated by PPARγ ligands (c). On these genes PPARγ may be recruited to the promoter by protein-protein interactions.