Differences In Mitochondrial Energy Metabolism Of Skeletal Muscle And Intervention Of Sodium Butyrate Between Two Obesity Phenotype Rats Induced By HFD

Mitochondria is the main organelle for cell energy metabolism and free radical production.Mitochondrial dysfunction is closely related to the occurrence and development of metabolic syndromes such as obesity,hyperglycemia,and hyperlipidemia.Therefore,it is important to maintain mitochondrial function.Obesity-prone(OP)and obesity-resistant(OR)individuals differ in energy metabolism,redox homeostasis etc,but the effect of mitochondrial homeostasis on different obesity phenotype is unclear.Butyrate,a volatile short chain fatty acids,is the byproduct of the fermentation of the intestinal anaerobic flora and easily combines with sodium to form sodium butyrate(NaB).Studies have confirmed that NaB can improve the activity of antioxidant enzymes in tissues,affect the metabolism of glucose and lipids and regulate mitochondrial metabolism.However,the specific mechanism is not clear yet.In the present study,we established different obesity phenotype rats,investigated the term changes of mitochondrial energy metabolism and redox homeostasis in skeletal muscles and clarified the regulatory mechanism and dose effect of NaB on skeletal muscle by NaB intervention.OP and OR rats induced by high-fat diet were sampled at 8th,14th and 20th weeks to analyze body weight,blood glucose,insulin levels and HOMA-IR index;determine redox related indicators of gastrocnemius and pancreas,mitochondrial antioxidant enzymes(GSH-px,Mn-SOD)activity,acetyl CoA,NADH/NAD~+ratio,ATP and lactic acid levels.The results showed that 8-20 weeks of high-fat diet resulted in oxidative stress in the gastrocnemius muscle and pancreas of OP rats,T-AOC,SOD and mitochondrial antioxidant enzyme levels were significantly reduced,ROS and MDA levels were increased,mitochondrial ATP production was insufficient and energy metabolism was weakened.Compared with OP rats,OR rats maintained strong mitochondrial energy metabolism function during high-fat diet for 8-14 weeks.In the whole feeding period,antioxidant-related indexes of skeletal muscle and pancreas of OR rats were significantly higher than those of OP rats.OP and OR rats fed high-fat diets for 8 weeks.The doses of NaB added to HFD for 12weeks were 4%,5%and 6%.NaB intervention could effectively protect the gastrocnemius muscle and pancreas from oxidative stress induced by high fat diet,upregulate T-AOC,antioxidant enzyme(SOD,GSH-px)activity and GSH/GSSG ratio,reduce ROS level and MDA content.NaB may increase the expression of PI3K,Nrf2,NQO-1,HO-1 mRNA expression and inhibit GSK-3βby regulating Nrf2 antioxidant pathway to enhance tissue antioxidant capacity.At the same time,NaB intervention could significantly increase the expression of Glut4 and IRS-1 mRNA in gastrocnemius muscle of OP and OR rats,suppress the expression of Bax and Casepase 3,increase the mRNA expression of Pdx1,Maf A and Bcl-2,and increase insulin secretion and muscle insulin sensitivity.The regulatory effect of NaB was significantly correlated with its significantly increased activity of mitochondrial antioxidant enzymes Mn SOD and GSH-px,mitochondrial membrane potential,NADH/NAD~+ratio,acetyl-Co A and ATP production,TFAM and PGC-1αexpression and mitochondrial DNA copy number.In addition,5%,6%NaB intervention in OP rats,4%,5%NaB intervention in OR rats were more significant,indicating that there were dose effects of NaB intervention in different obesity phenotypes,and the relevant mechanism needs to be further studied.