Antagonism of peroxisome proliferator-activated receptor γ prevents high-fat diet-induced obesity in vivo

Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been reported to play an important role to regulate adiposity and insulin sensitivity. It is not clear whether antagonism of PPAR gamma using a synthetic ligand has significant effects on adipose tissue weight and glucose metabolism in vivo. The aim of this study is to examine the effects of a synthetic PPAR gamma antagonist (GW9662) on adiposity and glycemic control in high-fat (HF) diet-fed mice. First the properties of GW9662 as a PPAR gamma antagonist were estimated in vitro. GW9662 displaced [H-3]rosiglitazone from PPAR gamma with K-i values of 13 nM, indicating that the affinity of GW9662 for PPAR gamma was higher than that of rosightazone (110 nM). GW9662 had no effect on PPAR gamma transactivation in cells expressing human PPAR gamma. Treatment of 3T3-L1 preadipocytes with GW9662 did not increase aP2 expression or [C-14]acetic acid uptake. GW9662 did not recruit transcriptional cofactors to PPAR gamma. Limited trypsin digestion of the human PPAR gamma/GW9662 complex showed patterns of digestion distinct from those of rosightazone. This suggests that the binding characteristics between GW9662 and PPAR gamma are different from those of rosightazone. Treatment of HF diet-fed mice with GW9662 revealed that this compound prevented HF diet-induced obesity without affecting food intake. GW9662 suppressed any increase in the amount of visceral adipose tissue, but it did not change HF diet-induced glucose intolerance. These data indicate that antagonism of PPAR gamma using a synthetic ligand suppresses the increased adiposity observed in HF diet-induced obesity, and that a PPAR gamma antagonist could possibly be developed as an anti-obesity drug. (c) 2006 Elsevier Inc. All rights reserved.