Title: Differential Effects of 17,18-EEQ and 19,20-EDP Combined with Soluble Epoxide Hydrolase Inhibitor t-TUCB on Diet-Induced Obesity in Mice.
Authors: Yang, Yang; Xu, Xinyun; Wu, Haoying; Yang, Jun; Chen, Jiangang; Morisseau, Christophe; Hammock, Bruce D; Bettaieb, Ahmed; Zhao, Ling
Published In Int J Mol Sci, (2021 Jul 31)
Abstract: 17,18-Epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive epoxides produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid and docosahexaenoic acid, respectively. However, these epoxides are quickly metabolized into less active diols by soluble epoxide hydrolase (sEH). We have previously demonstrated that an sEH inhibitor, t-TUCB, decreased serum triglycerides (TG) and increased lipid metabolic protein expression in the brown adipose tissue (BAT) of diet-induced obese mice. This study investigates the preventive effects of t-TUCB (T) alone or combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) on BAT activation in the development of diet-induced obesity and metabolic disorders via osmotic minipump delivery in mice. Both T + EDP and T + EEQ groups showed significant improvement in fasting glucose, serum triglycerides, and higher core body temperature, whereas heat production was only significantly increased in the T + EEQ group. Moreover, both the T + EDP and T + EEQ groups showed less lipid accumulation in the BAT. Although UCP1 expression was not changed, PGC1α expression was increased in all three treated groups. In contrast, the expression of CPT1A and CPT1B, which are responsible for the rate-limiting step for fatty acid oxidation, was only increased in the T + EDP and T + EEQ groups. Interestingly, as a fatty acid transporter, CD36 expression was only increased in the T + EEQ group. Furthermore, both the T + EDP and T + EEQ groups showed decreased inflammatory NFκB signaling in the BAT. Our results suggest that 17,18-EEQ or 19,20-EDP combined with t-TUCB may prevent high-fat diet-induced metabolic disorders, in part through increased thermogenesis, upregulating lipid metabolic protein expression, and decreasing inflammation in the BAT.
PubMed ID: 34361032
MeSH Terms: Adipogenesis; Adipose Tissue, Brown/cytology; Adipose Tissue, Brown/drug effects; Adipose Tissue, Brown/metabolism; Animals; Anti-Obesity Agents/administration & dosage; Anti-Obesity Agents/pharmacology; Anti-Obesity Agents/therapeutic use*; Arachidonic Acids/administration & dosage; Arachidonic Acids/pharmacology; Arachidonic Acids/therapeutic use*; Benzoates/administration & dosage; Benzoates/pharmacology; Benzoates/therapeutic use*; Blood Glucose/metabolism; Carnitine O-Palmitoyltransferase/metabolism; Diet, High-Fat; Epoxide Hydrolases/antagonists & inhibitors; Fatty Acids/metabolism; Male; Mice; Mice, Inbred C57BL; NF-kappa B/metabolism; Obesity/drug therapy*; Obesity/etiology; Obesity/metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism; Phenylurea Compounds/administration & dosage; Phenylurea Compounds/pharmacology; Phenylurea Compounds/therapeutic use*