Inhibition of soluble epoxide hydrolase reduces food intake and increases metabolic rate in obese mice

Background and aims: This study evaluated the responses to soluble epoxide hydrolase (s-EH) inhibition, an essential enzyme in the metabolism of arachidonic acid, on food intake, body weight and metabolic parameters in mice fed a high fat-high fructose diet (HFD) for 10 weeks. Methods and results: After 5 weeks of HFD, mice were divided into two groups: 1) s-EH inhibitor (AR9281, 200 mg/kg/day by gavage twice daily), and 2) vehicle (0.3 ml per gavage). Food intake, body weight, oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory quotient (RQ), and motor activity were measured weekly for more 5 weeks. HFD increased body weight (37 perpendicular to 1 vs. 26 perpendicular to 1 g), and plasma of glucose (316 perpendicular to 8 vs. 188 perpendicular to 27 mg/dl), insulin (62.1 +/- 8.1 vs. 15.5 +/- 5.0 mu U/ml), and leptin levels (39.4 +/- 3.6 vs. 7.5 +/- 0.1 ng/ml) while reducing VO2, VCO2 and motor activity. s-EH inhibition for 5 weeks decreased caloric intake by similar to 32% and increased VO2 by similar to 17% (42.8 +/- 1.4 vs. 50.2 +/- 1.5 ml/kg/min) leading to significant weight loss. Inhibition of s-EHi also caused significant reductions in plasma leptin levels and visceral fat content. Uncoupling protein 1 (UCP1) content in brown adipose tissue was also elevated by similar to 50% during s-EH inhibition compared to vehicle treatment. Conclusion: These results suggest that s-EH inhibition with AR9281 promotes weight loss by reducing appetite and increasing metabolic rate, and that increased UCP1 content may contribute to the increase in energy expenditure. (C) 2010 Elsevier B.V. All rights reserved.