| Nowadays, the incidence of obesity is increasing gradually, endangering human beings seriously.Obesity has been demonstrated to be associated with lipid metabolic disorder and insulin resistance.Insulin resistance is the common nosogenesis of the diseases type 2 diabetes, hypertension and AS.Therefore, it is beneficial to find target and associated drug for curing obesity, improving lipid metabolism dysfunction and insulin resistance.Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors, which belong to the super family of the nuclear receptor family. The PPARs play an important part in controlling glucose and lipid homeostasis, by regulating the expression of a large number of genes.There are there related PPAR family members:PPARa, PPARy and PPARβ/δ. PPARαis hightly expressed in liver, and mainly regulates lipid metabolism, Synthetic ligands for PPARα, are used for the treatment of hyperlipidemia.PPARγis abundant in adipose tissue, improving the sensitivity of the tissues to the insulin.Synthetic ligands for PPARy are used for the treatment of type 2 diabetes. PPARβ/δis ubiquitously expressed, however, the physiological role of PPARβ/δis still unclear completely. The availability of potent and specific agonists for PPARβ/δrevealed an important contrition of this isotype in glucose and lipid metabolism regulation and also pointed the nuclear receptor may be a potential target for the intervention and prevention of obesity and type 2 diabetes.In this paper, the activation of new compounds on PPARs were assayed by dual-luciferase reporter gene assay. In vivo, the effect of lipid metabolism were assessed in DIO mice assay. And the regulation mechanism of the compounds on lipid metabolism were investigated on the PPAR transcriptional regulation level.Firstly, The EC50 of new compounds were evaluated with the dual-luciferase reporter gene assay.The results showed that F3SM and F3SMDM have similar function to activate PPARβ/δcompared to GW501516.Meanwhile,in some extent,they are also potent activator for PPARα.In order to study the role of PPARβ/δagonists in the regulation of lipid metabolism, we detected body weight changes, glucose tolerance test, insulin tolerance test, lipid levels in DIO mice model.The result showed that F3SM 5mg/kg may be the optimal dose for further study.we re-established DIO mice model, the pharmacological effects and mechanisms of F3SM and F3SMDM was studied systematicly. During the experiment, the weight of DIO mice, postprandial blood glucose were monited, and glucose tolerance test were assessed.In the end of the experiment perirenal adipose tissues and liver were removed and weighed. Plasma TG, TC, HDL-c and FFA were determined using corresponding kits. Content of mice liver slices to observe the results of HE staining, The glucogen, triglyceride and total cholesterol in the mice liver were determined by enzymetical kits.The quantitive analyses of mRNA expression of genes related to metabolism were performed by real-time PCR. The proteins of insulin receptors and GLUT4 in skepletal muscle were determined by Western blot. The results showed that F3SMDM can persistently reduce fat content of DIO mice resulting reduction of body weight, F3SM and F3SMDM may decrease the postprandil blood gloucose of DIO mice, F3SMDM may ameliorate the abnormality of glucose tolerance, F3SM and F3SMDM can significantly decrease plasma TG, F3SMDM can significantly decrease plasma FFA, F3SM may significantly reduce triglyceride in liver in DIO mice.F3SM and F3SMDM can increase glucogen in liver in DIO mice.In conclusion, F3SM and F3SMDM significantly activate PPARβ/δin vitro and have reduction in postprandial blood glucose and TG in DIO mice model.Their broad pharmacological effect remains to be further explored, in order to prove their potential medicinal value.
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