title: Antiobesity Effect of a Small Molecule Repressor of RORγ.
abstract: 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.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Chang
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Khan
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Dana S
authors.initials: DS
authors.lastname: Kuruvilla
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Ruben
authors.initials: R
authors.lastname: Garcia-Ordonez
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Corzo
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Thaddeus J
authors.initials: TJ
authors.lastname: Unger
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: David W
authors.initials: DW
authors.lastname: White
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Susan
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.).
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.R.C., Y.H., T.M.K., D.S.K., R.G.-O., C.A.C., S.K., L.L., M.D.C., Th.M.K., P.R.G.); and Ember Therapeutics, Watertown, Massachusetts (T.J.U., D.W.W.) pgriffin@scripps.edu.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D059305:Diet, High-Fat; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D019440:Anti-Obesity Agents; D001713:Biphenyl Compounds; D007328:Insulin; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010879:Piperazines; C539901:Rorc protein, mouse; C000600173:SR1555; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors