RT Journal Article SR Electronic T1 Antiobesity Effect of a Small Molecule Repressor of RORγ JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 48 OP 56 DO 10.1124/mol.114.097485 VO 88 IS 1 A1 Mi Ra Chang A1 Yuanjun He A1 Tanya M. Khan A1 Dana S. Kuruvilla A1 Ruben Garcia-Ordonez A1 Cesar A. Corzo A1 Thaddeus J. Unger A1 David W. White A1 Susan Khan A1 Li Lin A1 Michael D. Cameron A1 Theodore M. Kamenecka A1 Patrick R. Griffin YR 2015 UL http://molpharm.aspetjournals.org/content/88/1/48.abstract AB The orphan nuclear receptor RORγ is a key regulator for T helper 17 (TH17) cell differentiation, which regulates metabolic and circadian rhythm genes in peripheral tissues. Previously, it was shown that the small molecule inverse agonist of RORγ SR1555 [1-(4-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)piperazin-1-yl) ethanone] suppressed TH17 differentiation and stimulated induced T regulatory (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.