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Peroxisome proliferator-activated receptor γ (PPARγ) has been reported to play an important role to regulate adiposity and insulin sensitivity. It is not clear whether antagonism of PPARγ 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 PPARγ antagonist (GW9662) on adiposity and glycemic control in high-fat (HF) diet-fed mice. First the properties of GW9662 as a PPARγ antagonist were estimated in vitro. GW9662 displaced [3H]rosiglitazone from PPARγ with Ki values of 13 nM, indicating that the affinity of GW9662 for PPARγ was higher than that of rosiglitazone (110 nM). GW9662 had no effect on PPARγ transactivation in cells expressing human PPARγ. Treatment of 3T3-L1 preadipocytes with GW9662 did not increase aP2 expression or [14C]acetic acid uptake. GW9662 did not recruit transcriptional cofactors to PPARγ. Limited trypsin digestion of the human PPARγ/GW9662 complex showed patterns of digestion distinct from those of rosiglitazone. This suggests that the binding characteristics between GW9662 and PPARγ are different from those of rosiglitazone. 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 PPARγ using a synthetic ligand suppresses the increased adiposity observed in HF diet-induced obesity, and that a PPARγ antagonist could possibly be developed as an anti-obesity drug.