A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation

The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPAR gamma subt ype plays a central role in the regulation of adipogenesis and is the molec ular target for the 2,4-thiazolidinedione class of antidiabetic drugs. Stru ctural studies have revealed that agonist ligands activate the PPARs throug h direct interactions with the C-terminal region of the ligand-binding doma in, which includes the activation function 2 helix. GW0072 was identified a s a high-affinity PPAR gamma ligand that was a weak partial agonist of PPAR gamma transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. Thes e results establish an approach to the design of PPAR ligands with modified biological activities.