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.
Footnotes
- Received December 18, 2014.
- Accepted April 22, 2015.
This work was supported in part by the by the Intramural Research Program of the National Institutes of Health National Institute of Mental Health [Grant U54-MH074404].
None of the authors have conflicts of interest with the work presented in this paper. P.R.G. was a cofounder of Ember Therapeutics, which has recently undergone a merger and P.R.G. is no longer associated with the new company. T.J.U. and D.W.W. were (but are no longer) employees of Ember Therapeutics.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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