Peroxisome proliferator-activated receptor-gamma (PPARgamma) and -delta (PPARdelta) are major regulators of fat metabolism. They belong to the nuclear receptor super-family of ligand activated transcription factors. Highly selective PPARgamma and PPARdelta ligands are promising drugs or drug candidates for the treatment of type 2 diabetes and obesity. However, the molecular mechanism by which these ligands act as anti-diabetes and/or anti-obesity agents has largely remained unclear. The tripartite nature of the nuclear receptor biology suggests that the biological effect of a ligand is determined by the combinatorial collaboration among these three parts: ligand, nuclear receptor, and cofactors (coactivators or corepressors) recruited by ligand-bound nuclear receptor on the target gene promoters. To understand the molecular mechanism by which ligand-activated PPARgamma and PPARdelta transcriptionally regulate fat metabolism, three projects using proteomic and genomic approaches have been initiated:? ? I: Isolation and characterization of a histone methyltransferase complex that regulates PPARgamma transcriptional activity. ? ? II: Isolation and characterization of transcription cofactors for PPARdelta. ? ?
