PPARgamma is an important nuclear receptor transcription factor which promotes adipogenesis and influences insulin sensitivity. A class of insulin sensitizers, the thiazolidenediones, act as agonist ligands for PPARgamma. Paradoxically, reduced receptor levels are associated with decreased insulin resistance. There are an increasing number of examples where adipogenesis and insulin sensitivity are found to be similarly dissociated. This raises the possibility that PPARgamma's role as a transcriptional repressor may be important in contributing to adipocyte function and insulin sensitivity. Phosphorylation of the A/B domain of PPARgamma is associated with repression of PPAR-mediated transcription. We propose that corepressors are recruited by PPARgamma both in cells undergoing adipogenesis and in mature adipocytes. We plan to show that this recruitment leads to decreased expression of genes involved in adipogenesis and insulin sensitivity. In addition, we hypothesize that recruitment of corepressors may be triggered or enhanced by phosphorylation of PPARgamma.
