Inhibition of soluble epoxide hydrolase reduces food intake and increases metabolic rate in obese mice
2012
do Carmo, J.M. | da Silva, A.A. | Morgan, J. | (Jim) Wang, Y.-X. | Munusamy, S. | Hall, J.E.
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, 200mg/kg/day by gavage twice daily), and 2) vehicle (0.3ml 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±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 VO₂, VCO₂ and motor activity. s-EH inhibition for 5 weeks decreased caloric intake by ∼32% and increased VO₂ 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. 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.
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