OBJECTIVE 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. RESULTS After 5 weeks of HFD, mice were divided into two groups: 1) s-EH inhibitor (AR9281, 200mg/kg/day by gavage twice daily), and 2) vehicle (0.3ml per gavage). Food intake, body weight, oxygen consumption (VO(2)), carbon dioxide production (VCO(2)), respiratory quotient (RQ), and motor activity were measured weekly for more 5 weeks. HFD increased body weight (37±1 vs. 26±1g), and plasma of glucose (316±8 vs. 188±27mg/dl), insulin (62.1±8.1 vs. 15.5±5.0μU/ml), and leptin levels (39.4±3.6 vs. 7.5±0.1ng/ml) while reducing VO(2), VCO(2) and motor activity. s-EH inhibition for 5 weeks decreased caloric intake by ~32% and increased VO(2) by ~17% (42.8±1.4 vs. 50.2±1.5ml/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 ~50% during s-EH inhibition compared to vehicle treatment. CONCLUSIONS 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.