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Pharmacological inhibition of soluble epoxide hydrolase promotes brown adipogenesis
Author(s) -
Overby Haley,
Kearns Jamie,
Hildreth Kelsey,
Chahed Samah,
Kodani Sean,
Morisseau Christophe,
Hammock Bruce,
Wang Shu,
Bettaieb Ahmed,
Zhao Ling
Publication year - 2018
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.2018.32.1_supplement.560.4
Subject(s) - epoxide hydrolase 2 , thermogenin , adipogenesis , chemistry , brown adipose tissue , white adipose tissue , prdm16 , thermogenesis , medicine , docosahexaenoic acid , adipose tissue , endocrinology , biochemistry , autocrine signalling , eicosapentaenoic acid , polyunsaturated fatty acid , fatty acid , biology , enzyme , receptor
Brown adipose tissue (BAT) has emerged as a novel target for obesity treatment and prevention. In contrast to white adipocytes, brown adipocytes are responsible for nonshivering thermogenesis, in which ATP synthesis is uncoupled from respiration via uncoupling protein 1 (UCP1) leading to heat production. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that converts epoxy fatty acids (EpFAs) into less active diols. EpFAs are produced by cytochrome P‐450 epoxygenases from polyunsaturated fatty acids, such as arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid (DHA). Many EpFAs are autocrine/paracrine lipid signaling molecules that play important roles in physiological processes, including inflammation, vascular dilation, and cell growth and differentiation. Thus, sEH has become a pharmacological target and small and potent sEH inhibitors that stabilize endogenous EpFAs have been shown to be beneficial for many chronic diseases. The objectives of our studies are to study the regulation of sEH expression and the effects of sEH inhibitors on brown adipogenesis. We found that sEH expression was increased during differentiation of both murine and human brown adipocytes. sEH mRNA levels were significantly increased in the interscapular BAT, but not in the epididymal white adipose tissue (WAT), of diet‐induced obese mice. Moreover, sEH pharmacological inhibition using trans‐4‐{4‐[3‐(4‐trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid) (t‐TUCB) and trans‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐cyclohexyloxy]‐benzoic acid (t‐AUCB) dose‐dependently promoted brown adipocyte differentiation, possibly through activating PPAR gamma and alpha. In agreement with these findings, our studies further demonstrated higher UCP1 and PRDM16 protein expression in the interscapular BAT under basal conditions in the sEH knockout (KO) mice compared to the wild type (WT) controls. Moreover, the increases in mRNA expression of brown marker genes in response to cold exposure were enhanced in the interscapular BAT and subcutaneous WAT of the sEH KO mice compared to the WT controls. sEH deficiency further enhanced the induction of brown marker mRNA expression by t‐TUCB and 19, 20‐EDP, the most abundant EpFA derived from DHA. Together, our findings suggest that sEH may regulate brown adipogenesis and its inhibition could be novel therapeutic strategies to increase BAT development and thermogenesis. Support or Funding Information The work was partially supported by NIH R15AT008733 (to L.Z. and S.W.), NIH K99DK100736 (to A.B.), R00DK100736 (to A.B.), R01ES002710 (to B.D.H), P42ES004699 (to B.D.H), and T32GM099608 (to S.D.K). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .