A Novel Potent Antagonist of Peroxisome Proliferator-Activated Receptor γ Blocks Adipocyte Differentiation But Does Not Revert the Phenotype of Terminally Differentiated Adipocytes

The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). Their antihyperglycemic effects seem to be linked to the regulation of PPARγ-responsive genes. Here, we report the characterization of a specific PPARγ antagonist that blocks several of the biological activities of the PPARγ agonist rosiglitazone. PD068235 inhibited rosiglitazone-dependent PPARγ transcriptional activity with an IC50 of 0.8 μm and rosiglitazone-stimulated in vitro coactivator association. The role of PPARγ in the initiation of differentiation is well documented. In this study, we used PD068235 as a tool to evaluate the functional role of PPARγ in the maintenance of the terminally differentiated state. Treatment of confluent, growth-arrested 3T3-L1 preadipocytes with PD068235 blocked adipocyte differentiation induced by the standard adipogenic hormonal mixture (insulin/dexamethasone/isobutylmethylxanthin) and fully anta...