Preliminary Mechanism Of Dapagliflozin Promoting Fatty Acid Oxidation In Liver Of Obese Mice Induced By High Fat

Objective:In this study,the body weight and fasting plasma glucose,serum insulin,cholesterol content and triglyceride content in serum and liver,glucose tolerance test and insulin tolerance test,hematoxylin-eosin(HE)staining of liver,liver weight and fat mass of mice in each group were detected before and after the research.The objective of this experiment was to study the primary mechanism of Dapagliflozin promoting fatty acid oxidation in liver of obese mice induced by high fat.(1)The effects of Dapagliflozin on fatty acid oxidation in liver of obese mice were systematically studied by establishing an animal model of high-lipid-induced obesity mice.(2)To explore the mechanism of Dapagliflozin in improving liver lipid metabolism through SIRT1,PGC-1a and CPT1A related signaling pathways and by increasing the decomposition of liver fatty acids.(3)To investigate the mechanism of reducing body weight,liver and fat weight and improving insulin resistance by increasing urinary glucose excretion.Methods:We choose 24 strong male mice of C57BL/6 genotypes,between six and seven weeks of age.All mice were raised in cages,fed with standard pellet feed,and were free to drink purified water at ambient temperature(25±2)℃.Before the experiment,all mice were adaptively fed for 1 week.Two groups of T2DM mice were fed high-fat diet for 12 weeks(OC group and Dapagliflozin group as model control group),and the other group was fed lowfat diet as normal control group(NC group).Dapagliflozin group was given gavage of Dapagliflozin 10mg/kg/d for 21 consecutive days,NC group and OC group were intraperitoneally injected with the same amount of normal saline,respectively.During administration,body weight and glucolipid metabolism of mice in each group were recorded.After the experiment,the liver of mice was taken immediately,and the weight of liver and fat of mice was weighed.Serum insulin and lipid levels were detected by ELISA.Western blot and Real-time PCR were used to detect the protein expression levels of SIRT1,PGC-1a and CPT1A related pathways in liver of mice.Results:Compared with OC group,the body weight,fat content,serum insulin and lipid levels in Dapagliflozin group were significantly decreased after 3 weeks of treatment(P<0.05),glucose and insulin tolerance levels were significantly increased(P<0.05).In addition,liver weight and lipid content decreased(P<0.05),SIRT1,PGC-1a and CPT1A gene and protein levels in liver were significantly increased(P<0.05).Conclusion:Dapagliflozin plus high fat can induce urine glucose excretion,reduce fat accumulation in body and liver,and reduce liver weight and body weight in obese mice.Dapagliflozin could increase the sensitivity of liver to insulin by lifting glucose oxidative metabolism in obese mice.By promoting fatty acid decomposition and increasing fatty acid oxidation,Dapagliflozin can alleviate the lipid metabolism of liver in obese mice induced by high fat.Through molecular level detection,it was illustrated that the fundamental principles of Dapagliflozin which improving the lipid metabolism of liver may be correlated with the excitation of liver SIRT1/PGC-1a/CPT1A pathway.