Modulatory Effect Of Poly(I:C) Induced Innate Immunity On The Pathogenesis Of Insulin Resistance And The Relevant Mechanism

Objective:To investigate the modulatory effect of innate immunity on the pathogenesis of insulin resistance induced by high fat diet feeding.Methods:In this study,C57BL/6J mice were performed for experimental model of insulin resistance fed with high fat diet for 12 weeks,while normal chow diet fed mice were added as wild type control.Meanwhile,high fat died fed mice were received introperitoneal injection with Poly(I:C)and PBS,respectively.For each mouse,fasting blood glucose and body weight were measured per week,and cytokines including IL-4,IL-10,TNF-α and IFN-γ were measured by cytometric bead array.By the end of 12 weeks,postprandial insulin response and regulatory T cell percentage were detected in each mouse.Furthermore,changed p-Akt/Akt ratios of liver,muscle and fat were examined after insulin challenge via western blot analysis.q RT-PCR was used for measuring m RNA expressions of Glut1 and Glut4 genes in each mouse liver,muslce and fat after injected with glucose.CD4+ T cells were isolated from high fat diet fed mice and used for in vitro experiments.Isolated CD4+ T cells were insulted with TNF-α,IL-6 and TGF-β,and were analysed for the protein expression of p-STAT3 and STAT3.Protein expression of TLR3,specific receptor for Poly(I:C)was confirmed in mose insulinoma cells(MIN-6 and NIT-1),as well as accompanied changes of p-Akt and Akt protein exrepssion in different glucose concentraion of culture conditions.Results:Poly(I:C)treatment contributes to the decrease of pro-inflammatory cytokine level and the increase of anti-inflammatory cytokine level,which associated with alleviating the inflammatory status of insulin resistance.However,Poly(I:C)promotes glucose homeostasis and immune tolerance by increasing postprandial insulin response and regultory T cell percentage,while the proliferation of activated CD4+ T cell was not affected.Compared with high fat diet fed mice treated with PBS,Poly(I:C)precondition enhanced p-Akt/Akt ratios in liver,muscle and fat after insulin challenge.Besides,m RNA expressions of Glut1 and Glut4 genes were increased in liver,muscle and fat among high fat diet fed mice due to Poly(I:C)treatment.As the specific receptor for Poly(I:C),TLR3 leads to phosphorylation of Akt protein in mouse insulinoma cells and this role is independent of glucose concentration of culture conditions.Conclusions:Poly(I:C)treatment plays a crucial role in the course of antigen presentation,which sequently contributes to the established innate immune memory.Initially,innate immune memory is harmful based on the increased accumulation of adipose tisse during a high fat diet feeding.By the contrary,insulin resistance may be a protective adaptation according to the instinctive defense.