The Effect And Mechanism Of Exercise Combined With Hyperthermia On Glucose And Lipid Metabolism In FNDC5 Knockout IR Rats

Insulin resistance caused by obesity and sedentary lifestyle?IR?is the basis of the occurrence and development of type 2 diabetes,in addition,it is also an independent risk factor for metabolic diseases such as coronary heart disease,thrombosis and so on.Irisin plays an important role in the occurrence and development of metabolic diseases such as IR:On the one hand,the increase of Irisin can up-regulate the expression of PRDM16 and interact with PGC-1?,so as to stimulate the expression of UCP1 and improve lipid metabolism.On the other hand,Irisin can activate the activity of Akt protein and promote its phosphorylation,so as to increase the translocation of GLUT4 to cell membrane,increase glucose uptake and improve glucose metabolism.Exercise,as a cost-effective and non-toxic and side-effect-free"green"non-drug intervention method,has been widely used in the prevention and treatment of IR-related metabolic diseases,but its specific biomolecule mechanism has not been fully clarified.In the previous study of the research group,it was found that the positive effects of exercise alone,high temperature alone and exercise combined with high temperature intervention on IR rats depended on the activation of Irisin metabolic pathway.Exercise combined with high temperature had the best effect on glucose and lipid metabolism in IR rats.However,whether Irisin metabolic pathway is a key pathway in the effect of exercise or high temperature on IR is worthy of further study.Objective:In order to verify whether the metabolic pathway of Irisin is a key pathway in the effect of exercise or high temperature on IR,and to further explain the molecular mechanism of exercise combined with high temperature in the prevention and treatment of IR,FNDC5 gene knockout rats?exercise induces the expression of FNDC5 protein in skeletal muscle by up-regulating PGC-1?,which produces a small peptide under the action of proteolytic enzyme hydrolysis and cleavage--Irisin?,by feeding it with a high-fat diet for 8 weeks to establish the IR model.Choosing the best intervention method to improve IR effect in the early stage,exercise combined with high temperature intervention,a 7-week intervention experiment was carried out in successful rats,and was used to observe the effect of combined high temperature on glucose and lipid metabolism of FNDC5 gene knockout IR rats,and the molecular mechanism was discussed by detecting the index of protein related to glucose and lipid metabolism.Method:Thirty-four 8-week-old male FNDC5 knockout rats were randomly divided into two groups:hyperlipidemia group?n=26?and general diet group?n=8?.The hyperlipidemic group was fed with high-fat diet and the general diet group was fed with routine feeding.IR model was established by feeding with high-fat diet for 8 weeks.The blood glucose?FBG?,fasting insulin?FINS?,leptin?LEP?and adiponectin?ADP?levels were measured at the end of the modeling,and the Insulin Resistance Index?HOMA-IR?and insulin sensitivity index?ISI?were calculated.Oral glucose tolerance test?OGTT?was performed to calculate the area under OGTT blood glucose curve(AUC_BG)to determine whether the IR model was established successfully.After the successful establishment of the model,FNDC5 gene knockout IR rats were randomly divided into exercise combined with hyperthermia group?IFE?and quiet control group?IFC?,IFE group for 7 weeks of exercise combined with hyperthermia intervention.That is,rats perform65%-75%VO_2max treadmill exercise in a special environment laboratory at 38?.The first training time is 1 minute,1 time per day,and then the daily exercise time increases by 2 minutes until 31minutes/time,maintain this amount of training,rest on Sundays.IFC group was fed routinely.After 7weeks of intervention,the levels of FBG,FINS,LEP and ADP were measured,and the ratios of ADP/LEP,ISI and HOMA-IR were calculated.The levels of total cholesterol?TC?,triglyceride?TG?,high density lipoprotein cholesterol?HDLc?and low density lipoprotein cholesterol?LDLc?were measured.The perirenal fat,epididymal fat and scapular fat were isolated,the indexes of perirenal fat,epididymal fat and scapular fat were calculated.Separate soleus muscle,extensor digitorum longus muscle and brown fat,to detect the expression of peroxisome proliferator-activated receptor?coactivator 1-??PGC-1??,uncoupling protein 1?UCP1?,PR domain protein 16?PRDM16?,protein kinase B?Akt?,p-Akt and glucose transporter 4?GLUT4?in soleus muscle and extensor digitorum longus muscle.Results:1.Compared with the Wistar rats in the general diet group,the body weight,FBG and FINS,LEP levels,HOMA-IR,OGTT blood glucose levels and AUCBG in the FNDC5 gene knockout hyperlipidemia group and the Wistar rats in the hyperlipidemia group were significantly increased?P<0.01?.And ADP level,ADP/LEP and ISI were decreased significantly?P<0.01?.That is to say,indicated that the modeling was successful.2.The probability of IR in FNDC5 group increased with the increase of age.3.Success rate of IR,modeling in 21 FNDC5 knockout rats 81%;The success rate of IR,modeling in 23 Wistar rats was 72%.4.There was no significant difference in the levels of FBG,FINS,TG,TC,LDLc and HDLc between IFC and IFE groups?P>0.05?before exercise combined with hyperthermia intervention.5.After 7 weeks of exercise combined with hyperthermia intervention,the body weight of IFE group was significantly lower than that of IFC group?P<0.05?,but there was no significant difference in perirenal fat index,epididymal fat index and scapular fat index between IFE and IFC groups?P>0.05?.6.After 7 weeks of intervention,the levels of FBG,FINS,ADP,LEP and HOMA-IR,ISI,ADP/LEP in IFE group were not significantly different compared with IFC group?P>0.05?,and there was no significant difference in TG,TC,LDLc and HDLc levels between the two groups?P>0.05?.7.After 7 weeks of exercise combined with hyperthermia intervention,there was no significant difference in the expression of PGC-1?,Akt,p-Akt,GLLUT4,UCP1 and PRDM16 protein in soleus muscle and extensor digitorum longus muscle between IFE and IFC groups?P>0.05?.Conclusion:?1?Exercise combined with hyperthermia intervention had no effect on glycolipid metabolism in FNDC5knockout IR rats.?2?This study found that Irisin should be the key hormone to mediate the effect of exercise on IR rats.