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Anti‐obesity effect of a small molecule repressor of RORγ
Author(s) -
Chang MiRa,
Kamenecka Theodore,
Griffin Patrick
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb479
Subject(s) - endocrinology , medicine , hormone , chemistry , thermogenesis , metabolic syndrome , nuclear receptor , inverse agonist , adipose tissue , agonist , receptor , biology , obesity , biochemistry , gene , transcription factor
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 and it was shown to regulate expression of a range of metabolic genes in liver cells. Here treatment of cultured pre‐adipocyctes with SR1555 led to increased expression of ROR , FGF21, and adipoQ while expression of RORγ was repressed. 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 ROR 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.