Eugenosedin‐A prevents hyperglycaemia,hyperlipidaemia and lipid peroxidation in C57BL/6J mice fed a high‐fat diet

Objectives Eugenosedin‐A is a serotonin (5‐hydroxytryptamine; 5‐HT) 5‐HT_{1b /2a} and _α1/α2/β1‐adrenoceptor blocker with anti‐oxidative, anti‐inflammatory and free‐radical scavenging activities. Previous reports demonstrated that 5‐HT_2a blockers could diminish hyperlipidaemia. This study therefore aimed to investigate the possible uses and mechanisms of eugenosedin‐A and other agents in treating hyperlipidaemia. Methods C57BL/6J mice were randomly divided into seven groups, fed a regular diet or a high‐fat diet alone or supplemented with one of five agents: eugenosedin‐A, ketanserin, prazosin, propranolol or atorvastatin (5 mg/kg p.o.) for 8 weeks. Key findings Compared with the regular diet, the mice fed the high‐fat diet had significantly higher body weight and glucose, insulin and lipid levels. Brain malondialdehyde concentration was increased and liver glutathione peroxidase activity decreased. Addition of eugenosedin‐A to the high‐fat diet resulted in less weight gain and reduced hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. Lipid and glucose homeostasis were related to decreased hepatic lipogenesis mRNAs and proteins (sterol regulatory element binding protein 1a, fatty acid synthase, sterol‐CoA desaturase) and restored adipose peroxisome proliferator‐activated receptor γ expression. Eugenosedin‐A also enhanced low‐density lipoprotein receptor mRNA expression. Conclusions Eugenosedin‐A may improve plasma lipid metabolism by increasing low‐density lipoprotein receptor and peroxisome proliferator‐activated receptor γ expression and diminishing sterol regulatory element binding protein 1a, fatty acid synthase and sterol‐CoA desaturase. Reduction of plasma glucose and lipid levels may, in turn, reduce insulin concentration, which would explain the marked improvement in obesity‐related hyperglycaemia and hyperlipidaemia. Furthermore, eugenosedin‐A affected malondialdehyde concentration and glutathione peroxidase activity, suggesting it may have anti‐peroxidation effects in mice fed a high‐fat diet.