Bone Marrow Macrophage-derived Exosomal MicroRNAs Regulate Insulin Resistance During Aging

Objective:Type 2 diabetes is typically characterized by insulin resistance,which causes a range of metabolic disorders.It is an aged-related disease that can occur at any age,but generally peaks among people aged 65 and above.The term "aged-associated insulin resistance" was first proposed in 1983,highlighting the strong correlation between aging and insulin resistance.The incidence of insulin resistance increases with aging.However,the underlying mechanisms of aged-related insulin resistance remain unclear.In addition,a large number of studies have confirmed that macrophages can be involved in the regulation of insulin sensitivity.Furthermore,our previous study showed that,bone,as an endocrine organ,can also participate in glucose metabolism.Based on the above research background,we explore the effect of bone marrow macrophage-derived exosomal micro RNAs on insulin sensitivity and its mechanism in the aging state.Method:We first compared the blood glucose,triglyceride content in blood and liver,liver weight to body weight ratio and other metabolic indicators of young(2 months old)and aged(24 months old)C57 mice.Then we extracted exosomes from cultured bone marrow macrophages of young and aged C57 mice and injected them into the tail vein of young mice(3months old)to detect glucolipid metabolism related indicators.Then,we selected mi R-378a-3p based on sequencing results,and overexpressed mi R-378a-3p in macrophage line RAW264.7.Exosomes overexpressing mi R-378a-3p were collected and injected into 2-month-old mice to detect glucolipid metabolism related indicators.Finally,we predicted the potential targets of mi R-378a-3p through biological websites,and verified by western blot(WB),real-time fluorescence quantitative PCR(q PCR)and biofunctional experiments.Results:We found that aged C57 mice showed significant insulin resistance and hepatic steatosis compared with young mice.Exosomes obtained from bone marrow macrophages of aged mice can cause glucose intolerance and insulin resistance.In exosomes highly enriched with mi RNAs,mi R-378a-3p was significantly elevated under aging,and overexpression of mi R-378a-3p in vivo or in vitro confirmed its adverse effects on insulin signaling pathway and glucose tolerance through PPARa.Conclusion:During aging,bone marrow macrophage-derived exosomes can impair insulin sensitivity.Mi R-378a-3p in exosomes plays a major role,and overexpression of mi R-378a-3p in vivo or in vitro can cause insulin resistance.