Gonadal White Adipose Tissue-derived Exosomal MiR-222 Promotes Obesity-associated Insulin Resistance

With the improvement of the level of substances,the incidence of obesity is increasing worldwide,which also leads to a large increase in the cases of diabetes.Diabetes mellitus is a heterogeneous metabolic disorder,and type Ⅱ diabetes mellitus(T2DM)accounts for more than 90% of its cases.Insulin resistance(IR)is the main symptom of T2 DM,and obesity is a common cause of IR.Adipose tissue can secrete several proinflammatory adipokines that cause insulin resistance due to obesity,and proinflammatory factors play an important role in the pathogenesis of obesity-induced IR.However,the limited effectiveness of treatments targeting these factors suggests that there are other mechanisms for insulin resistance.It has been reported that secretory mi RNA(exosomal mi RNAs)can be regarded as a novel adipocytokine,which is involved in the biogenesis and function of insulin.Micro RNAs are short,non-coding RNAs that bind to specific targeted m RNAs to suppress gene expression.Studies have found that not only a large number of mi RNAs exist in cells and tissues,but also a large number of stable mi RNAs are detected in the circulatory system.They exist in the exosomes at 50-200 nm,and the exosomes also contain m RNA and protein.Secreted mi RNAs,as important mediators of intercellular communication,can regulate biological processes in adjacent or distal tissues.In this study,we first established an obesity-induced insulin resistance mouse model fed with high-fat food(HFD)based on the results of the consistent up-regulation of secreted mi R-222 expression in serum of insulin resistance patients and obese people found in our previous laboratory.Significant increases in mi R-222 levels in serum,serum exosomes and gonadal adipose tissue were detected in HFD mouse models,and then experimental analysis showed that gonadal white adipose tissue(GWAT)was the main source of increased mi R-222 levels in serum of HFD mice.Then,we analyzed the target tissues of secreted mi R-222 derived from GWAT by constructing adenovirus vectors,and the results showed that secreted mi R-222 was mainly transported to liver and skeletal muscle tissues.Finally,we studied the mechanism of secreted mi R-222 in liver and skeletal muscle tissues through cell and animal experiments,and the results showed that secreted mi R-222 from GWAT inhibited the insulin signaling pathway by inhibiting the expression of IRS1 protein.In this study,we demonstrated that GWAT-derived secretory mi R-222 in obese mice could be a potential target for the treatment of obesity-related diseases and T2 DM.