Investigation Of The Effects Of Salidroside On Hepatic Insulin Resistance Via SIRT1/FoxO1 Signaling Pathway In Mice

Objective:To explore the effect and mechanism of salidroside on liver insulin resistance in mice.Methods:In the experiment,male C57BL/6J mice were used to prepare a high-fat-induced insulin resistance model.Mice were divided into normal group（NC）,high-fat model group（HFD）,pioglitazone group（PIO）,Rhodiola Tiangan low-dose group（SAL-L,）,medium-dose group（SAL-M）,and high-dose group（SAL-H）.All drug treatments were given by gavage into stomach as scheduled.NC group and HFD group were given 100 mg·kg^-1·d^-1normal saline;the PIO group was given 6.83 mg·kg^-1·d^-1 of pioglitazoneand;each dose group of salidroside was given 50（low）,100（medium）,or 200（high）mg·kg^-1·d^-1 salidroside.There were a total of 8 weeks of intragastric administration.During the gavage delivery treatment,body weight and random level of blood glucose were measured once every week.At the 7th and 8th week of administration,glucose tolerance test and insulin tolerance test were performed respectively.After 8 weeks,samples were taken,and blood was collected by heart puncture.FBG,TC,TG,LDL-C,HDL-C and FINS,C peptide,and glycosylated hemoglobin were measured with commercial kits.The liver was collected and placed in the sterile cryopreservation tubes and fixed in 4%paraformaldehyde for later use.The pathological changes of the liver were observed by HE staining.Real-time PCR method was used to detect the levels of SIRT1,FoxO1,FABP4,PPARγm RNA in mouse liver tissues.Western blotting was used to detect the protein expression of SIRT1,FoxO1,acely-FoxO1,FABP4,PPARγprotein in mouse liver tissues.Results:1.Salidroside reduced body mass in mice induced by high fat:the body weight of HFD group was always higher than that of NC group（P<0.05）.Compared with the HFD group,the body weight of mice in the salidroside groups and the PIO group was reduced（P<0.05）.2.Salidroside improved glucose and lipid metabolism disorders in mice:The blood glucose of HFD group mice was significantly higher than that of NC group mice（P<0.05）.The blood glucose of mice in each dose of salidroside and PIO group decreased（P<0.05）,and the change over time showed an overall downward trend.The salidroside dose group showed a dose-dependent effect on blood glucose,and the high-dose group had the most significant effect（P<0.05）.Compared with the NC group,the blood levels of TC,TG,LDL-C and HDL-C in the HFD group increased significantly（P<0.01）.After treatment,each dose of salidroside and the PIO group reduced the levels of TC,TG,and LDL-C in the serum（P<0.05）,and increased the level of HDL-C in the serum（P<0.05）.3.Salidroside reduced insulin resistance in mice:Compared with the NC group,the FINS,C-peptide,Hb A1c,and HOMA-IR of the HFD group were significantly increased（P<0.01）.Compared with the HFD group,the FINS,C peptide,Hb A1c,and HOMA-IR of the salidroside groups and the PIO group decreased（P<0.05）.In the glucose tolerance test and insulin tolerance test,compared with the NC group,the area under the curve in the HFD group was significantly increased（P<0.05）.Compared with the HFD group,the area under the curve in the salidroside groups and the PIO group was significantly higher Decrease（P<0.05）.4.Salidroside improved liver pathological damage in mice:The liver tissue structure of the HFD group was damaged,and the hepatocytes in the liver lobules had obvious fatty degeneration,and lymphocytes or neutrophils were scattered.The vacuolar degeneration of the liver in each dose group of salidroside and the PIO group was reduced,and the overall degree of disease was reduced to varying degrees.5.Salidroside reduced the m RNA expression of SIRT1、PPARγgens and increased the m RNA expression of FABP4 gens:Compared with the NC group,the expression of SIRT1 and PPARγwas significantly reduced in the HFD group（P<0.01）,and the expression level of FABP4 was significantly increased（P<0.01）.Compared with the HFD group,the expression of SIRT1 and PPARγincreased in each dose group of salidroside and the PIO group,and the expression level of FABP4 decreased,and the difference was statistically significant（P<0.01）.6.Salidroside reduced the protein expression of SIRT1、PPARγand increased the protein expression of acely-FoxO1、FABP4 protein:Compared with the NC group,the expression levels of SIRT1 and PPARγin the HFD group were significantly reduced（P<0.01）,and the expression levels of Acely-FoxO1 and FABP4 were significantly increased High（P<0.01）.Compared with the HFD group,the expression levels of SIRT1 and PPARγin the salidroside groups and the PIO group increased,and the expression levels of Acely-FoxO1 and FABP4 decreased,and the difference was statistically significant（P<0.01）.Conclusion:1.Salidroside could improve glucose and lipid metabolism disorders in insulin resistant mice.2.Salidroside could reduce insulin resistance in insulin resistant mice.3.Salidroside may play a role in reducing liver insulin resistance in mice by regulating the SIRT1/FoxO1 signaling pathway.