The Function And Mechanism Of Exercise Producing Lactate To Improve Obesity And Insulin Resistance

Objective: To explore the effects of short-term and long-term exercise intervention on insulin sensitivity and target organs in obese insulin-resistant mice,and clarify the molecular mechanisms of exercise-produced lactate regulates the expression of skeletal muscle insulin signaling pathway proteins and thermogenesis genes in adipose tissue via promoting the lactylation of PPARγ to improve insulin resistance in obesity.Methods: 1.Search Pub Med,Cnki and Wanfang database to collect relevant research on the relationship between exercise and energy metabolism in obesity.The retrieval time is from the establishment of the database to May 17,2021.Rev Man5.4 software was used to conduct Meta-analysis of the included studies;2.The obese insulin resistance model of C57BL/6J mice was established,and the mice were given short-term exercise intervention for 8 weeks.The body weight,body fat percentage,fat to body ratio of adipose tissue,morphology of subcutaneous inguinal white adipose tissue,blood lipid level,glucose tolerance,insulin tolerance,and expression levels of ir S-1 and AKT in skeletal muscle insulin signaling pathway were detected;3.The obesity-induced insulin resistance model mice were given 12-week long-term exercise intervention,and the body weight of the mice was measured.Body fat percentage,fat body ratio of each adipose tissue,subcutaneous inguinal white adipose tissue morphology,expression levels of adipose tissue thermogenic genes UCP-1 and Prdm16,blood lipid levels and glucose tolerance were detected;4.The obesity-induced insulin resistance model mice were administered exogenous lactate intervention,detect body weight,body fat ratio,fat body ratio of each adipose tissue,subcutaneous inguinal white adipose tissue morphology,adipose tissue thermogenic genes UCP-1,Prdm16 and Cidea expression levels,blood lipid levels and glucose tolerance;5.Molecule the binding sites of lactate and PPARγ protein were analyzed by docking,and the lactate level of PPARγ protein in adipose tissue of mice in exercise intervention and lactate intervention groups was detected by Co-IP.Results: 1.Meta-analysis was conducted to explore the relationship between exercise and energy consumption,and the results showed that exercise can not only promote energy metabolism of obese people,but also improve their resting energy metabolic rate,promote energy consumption and improve obesity status;2.Short-term exercise intervention had no significant effect on body weight,body fat percentage,fat body ratio of adipose tissue and the morphology of subcutaneous white groin adipose tissue of obese insulin resistance model mice,but could significantly reduce total cholesterol(TC)(P<0.001).Triglyceride(TG)(P<0.0001)and low density lipoprotein(LDL-C)(P<0.01)levels enhanced the systemic insulin sensitivity of model group mice.Meanwhile,short-term exercise intervention increased the phosphorylation level of skeletal muscle insulin signaling pathway protein AKT in model group mice(P<0.01).3.Long-term exercise intervention significantly reduced body weight(P<0.01),body fat percentage(P<0.05),subcutaneous inguinal white adipose tissue(SWAT)(P<0.01),epididymal white adipose tissue(ep WAT)(P<0.05).The lipid body ratio of dorsal white adipose tissue(BWAT)(P<0.01)and perirenal white adipose tissue(KWAT)(P<0.01)decreased the cell volume and increased the cell number of subcutaneous inguinal white adipose tissue(P<0.001),and increased the expression levels of thermogenic genes UCP-1 and Prdm16(P<0.01).Decreased TC(P<0.01),TG(P<0.0001)and LDL-C(P<0.05)levels,and still significantly enhanced the systemic insulin sensitivity of obese insulin resistance model mice.4.Both short-term and long-term exercise intervention could significantly increase serum lactic acid level in obese insulin resistance model mice,and lactic acid intervention could significantly reduce body weight(P<0.001),body fat percentage(P<0.001),FAT body ratio of SWAT(P<0.05)and BWAT(P<0.05)in obese insulin resistance model mice.Decreased the cell volume and cell number of subcutaneous inguinal white adipocytes(P<0.001),increased the expression levels of thermogenic genes UCP-1(P<0.05),Prdm16 and Cidea(P<0.05),decreased TC(P<0.01),TG(P<0.0001).Significantly increased systemic insulin sensitivity of obese insulin resistant mice;5.Molecular docking results showed that there was a binding site between lactic acid and PPARγprotein lysine 261,and the lactic acid structure was stable after analysis,and the immunoprecipitation results showed that exercise and lactic acid intervention can make PPARγ protein lactate modification in adipose tissue.Conclusion: 1.Both short-term and long-term exercise intervention can significantly increase systemic insulin sensitivity in obese insulin resistance model mice by enhancing skeletal muscle insulin sensitivity and promoting white fat cells of beige adipose tissue,reducing lipid accumulation and improving systemic insulin sensitivity,respectively.2.Lactic acid produced by exercise can improve insulin resistance in obesity by promoting the lactation of PPARγ protein and regulating the expression of downstream skeletal muscle insulin signaling pathway protein and adipose tissue thermogenic gene.