Effects of N-3 PUFA-Derived Epoxides Combined with sEH Inhibition on Brown Adipose Tissue and Brown Adipocytes in Obesity

Brown adipose tissue (BAT) has become a promising target for obesity treatment and prevention. However, effective dietary factors to promote BAT mass and function have not been identified. 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are two prominent epoxy fatty acids (EpFAs) produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. EpFAs are quickly metabolized to less active diols by soluble epoxide hydrolase (sEH). In this dissertation, the effects of an sEH inhibitor (t-TUCB) (which stabilizes EpFAs) alone or combined with n-3 EpFAs on thermogenic activity in the BAT and brown adipocytes in treating/preventing diet-induced obesity are investigated.

Using the mini osmotic pump delivery system, the effects of t-TUCB were studied in the obese mice. t-TCUB decreased serum triglycerides and increased perilipin protein expression in the BAT. Next, the effects of 19,20-EDP alone or combined with t-TUCB were investigated in diet-induced obese mice. 19,20-EDP alone or combined with t-TUCB did not improve body weight but improved the cold tolerance in the obese mice. We further investigated the effects of t-TUCB alone or combined with 19,20-EDP or 17,18-EEQ on BAT activation in preventing diet-induced obesity in mice. We found that 19,20-EDP or 17,18-EEQ combined with t-TUCB decreased the fasting glucose and serum triglycerides, in part through differentially regulating the thermogenic and lipid metabolic protein expression and inflammatory pathways in the iBAT of mice fed a high-fat diet. Finally, we investigated the effects of n-3 epoxides combined with t-TUCB on brown adipogenic differentiation and thermogenic capacity in murine brown adipocytes. We found that 19,20-EDP or 17,18-EEQ combined with t-TUCB promoted murine brown adipogenesis and mitochondrial respiration and uncoupling in vitro, which were accompanied by PPARγ activation and suppression of NFkB activation. Moreover, when combined with t-TUCB, 17,18-EEQ and 19,20-EDP differentially promote the thermogenic function of mature brown adipocytes.

In summary, sEH inhibition alone or combined with n-3 EpFAs may be beneficial in obesity-associated metabolic disorders through improving BAT activity by modulating thermogenic and lipid metabolic protein expression in mice. Moreover, 17,18-EEQ is more potent than 19,20-EDP in promoting brown adipocyte activity both in vitro and in vivo.