TY - JOUR T1 - Anti-Obesity Effect of a Small Molecule Repressor of RORγ JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.097485 SP - mol.114.097485 AU - Mi Ra Chang AU - Yuanjun He AU - Tanya Khan AU - Dana S. Kuruvilla AU - Ruben Garcia-Ordonez AU - Cesar Corzo AU - Thaddeus J. Unger AU - David W. White AU - Susan Khan AU - Li Lin AU - Michael D. Cameron AU - Theodore M. Kamenecka AU - Patrick R. Griffin Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/04/28/mol.114.097485.abstract N2 - The orphan nuclear receptor RORγ is a key regulator for TH17 cell differentiation and it regulates metabolic and circadian rhythm genes in peripheral tissues. Previously it was shown that the small molecule inverse agonist of RORγ SR1555 suppressed TH17 differentiation and stimulated iTreg cells. Here we show that treatment of cultured pre-adipocyctes with SR1555 represses the expression of RORγ while leading to increased expression of FGF21 and adipoQ. Chronic administration of SR1555 to obese diabetic mice resulted in a modest reduction in food intake accompanied with significant reduction in fat mass resulting in reduced body weight and improved insulin sensitivity. Analysis ex vivo of treated mice demonstrates that SR1555 induced expression of the thermogenic gene program in fat depots. Further studies in cultured cells showed that SR1555 inhibited activation of hormone sensitive lipase and increased fatty acid oxidation. Combined, these results suggest that pharmacological repression of RORγ may represent a strategy for treatment of obesity by increasing thermogenesis and fatty acid oxidation, while inhibition of hormone sensitive lipase activity results in a reduction of serum free fatty acids leading to improved peripheral insulin sensitivity. ER -