Mechanism Of SOCS2 Inhibits Mitochondrial Fatty Acid Oxidation In Mice Adipocytes

The cytokine signaling inhibitor SOCS2 is a member of the SOCS family and is widely expressed in muscle,nerves,pancreas and adipose tissue.A number of studies have shown that SOCS2 plays a key role in the body's physiological activities,such as fat deposition,skeletal muscle development,central nervous development,metabolism,immune response,breast development and other dependent cytokines.SOCS2 is a negative regulator of porcine fat cell GH signaling?which promotes fat synthesis to inhibit lipolysis?and inhibits mitochondrial synthesis of C2C12 cells.SOCS3 is a member of the SOCS family and has been shown to be a major negative regulator of Leptin and insulin signaling.Muscle overexpression of SOCS3 inhibits fatty acid oxidation and mitochondrial function of Leptin regulatory gene expression.SOCS3 regulates skeletal muscle Leptin resistance,leading to obesity individual fatty acid metabolic disorders.Although SOCS2 interacts with Leptin receptors.However,the specific function of interaction in different tissues requires further study.At the same time,the role of SOCS2 in fatty acid oxidation and the related molecular regulation mechanism have not been reported.The aim of this study was to investigate the molecular mechanism of SOCS2 in inhibiting mitochondrial fatty acid oxidation in mouse adipocytes.Get the following result:1.SOCS2 reverses the effect of Leptin on the oxidation of mouse fatty acids: 8 weeks old C57 BL / 6J male mice,injected with saline or 2.5?g / g of leptin for two weeks,SOCS2 adenovirus vector for one week.Leptin decreased the levels of FABP4,fatty acid synthase?FAS?and fatty acid transporter?FATP?,and increased the level of PGC1-?,and increased the level of FFA,Fatty acid transferase?FAT?protein level,CPT-1 activity and p-ACC level.SOCS2 inhibited the release of Leptin from free fatty acids?FFA?.Leptin increased serum TG and SOCS2 had no significant effect on TG,Leptin reduced the amount of palmitic acid produced by [14C];SOCS2 reduced the increased of [14C]-labeled palmitic acid to CO₂ production;SOCS2 reversed the down-regulation of FABP4 protein levels,increased CPT-1 activity and p-ACC and the level of Leptin receptor increased by Leptin.The above results indicated that SOCS2 reverse the effect of Leptin on the oxidation of fatty acids in mice.2.SOCS2 was used to regulate the fatty acid oxidation of mouse adipocytes induced by Leptin: The adipocytes of C57BL/6J mice were isolated and transfected with SOCS2 adenovirus vector.The expression of SOCS2 protein level in overexpression group was significantly increased,in other group was significantly decreased.SOCS2 reduced the levels of SOCS1 and SOCS3 mRNA,SOCS2 increased lipid accumulation and TG content,decreased FFA release;SOCS2 reduced mitochondrial fatty acid oxidation of key enzymes MCAD and LCAD activity,inhibition of Leptin receptor mRNA expression levels,decreased [14C]-labeled palmitic acid to CO₂ production.SOCS2 decreased the mRNA levels of PGC1-?,NRF-1,TFAM,AOX1,COX2 and UCP2,decreased the level of mitochondria complexI and complexIII,and decreased levels of p-ACC,p-JAK and CPT-1.SOCS2 inhibits Leptin receptor mRNA levels;Leptin-promoted p-ACC levels,and CPT-1 enzyme activity can be reduced by SOCS2,Leptin-enhanced levels of PGC1-?,Cyt C protein and mitochondrial ATP can be significantly reduced by SOCS2,and the level of Leptin-reduced FABP4 protein can be significantly enhanced by SOCS2;Leptin increased the amount of FFA released and the amount of [14C]-labeled palmitic acid to CO₂ production can be significantly reduced by SOCS2.It was found that SOCS2 was a negative regulator of fatty acid oxidation of adipocytes,SOCS2 could reverse the regulation of Leptin-promoted mouse adipocytes Fatty acid oxidation.3.SOCS2 inhibits fatty acid oxidation by suppressing leptin signaling.Adipose is a respiratory chain phosphorylation inhibitor that inhibits mitochondrial oxidative function by completely reducing mitochondrial ATP levels.SOCS2 overexpression increases the inhibitory effect of Oligomycin on the respiratory chain,knockout SOCS2 increases ATP production and [14C]-labeled CO₂ content,thereby repairing mitochondrial oxidation;The levels of p-JAK,p-ACC and CPT-1 were decreased in the overexpression of SOCS2.Coumermycin A1 is an inducer of JAK2 signaling pathway,Coumermycin A1 increases JAK2 phosphorylation level and increases CO₂ production;SOCS2 reduced the mRNA levels of Leptin receptor;SOCS2 reduced the p-ACC level induced by Coumermycin A1,and increased the level of CPT-1 enzyme activity and [14C]-labeled CO₂ production;SOCS2 increased the level of FABP4 which is decreased by Coumermycin A1;That is,on the basis of the Oligomycin and Coumermycin A1 models,SOCS2 reduces the LepR-JAK2 signaling pathway in fatty acid oxidation.In this study,to study the effect of SOCS2 on fatty acids oxidation in mice and the effect of SOCS2 on the fatty acid oxidation of mice under Leptin treatment.It was confirmed that SOCS2 inhibited the adipocytes fatty acid oxidation in mice by LepR-JAK2 signaling pathway.To lay the foundation for further study of SOCS2 and to provide reference for the treatment of some related metabolic diseases.