Anti‐Inflammatory and Antidiabetic Roles of PPARγ

The peroxisome proliferator-activated receptor γ (PPAR) regulates adipocyte differentiation and glucose homeostasis and is the molecular target of thiazolidinediones (TZDs) that act as insulin-sensitizers in patients with type 2 diabetes. PPARγ is also expressed in macrophages and negatively regulates the program of macrophage activa- tion by repressing a subset of AP1 and NK-κB-dependent genes. Recent genetic, molecu- lar and biochemical studies support the idea that PPARγ inhibits infl ammatory gene expression in activated macrophages by a NCoR/sumoylation-dependent pathway. Sumoylation of PPARγ targets it to NCoR corepressor complexes that are bound to infl ammatory response gene promoters and prevents their signal-dependent clearance that is normally a prerequisite for transcriptional activation. As a consequence, genes remain in a repressed state. Because the ligand-induced allosteric changes that promote entry of PPARγ into this transrepression pathway are distinct from those that mediate interactions with conventional coactivators, these fi ndings may facilitate the develop- ment of novel PPARγ ligands that retain antidiabetic activities but have reduced side effects.