Abstract: Objective To investigate the role of Toll-like receptor(TLR4)in insulin resistance and the effect of TLR4 on inflammatory cytokine expression in aortic artery in mice with insulin resistance(IR).Methods Forty-five male C57BL/6 mice (21 days old) were randomly divided into three groups (15 in each group):a control group fed with basic diet (low fat diet,LFD),a high fat diet control group (HFD-C)and a TAK-242 treatment group (HFD-T)both fed with high fat diet.Seven months after the treatments,glucose tolerance test (GTT) and insulin tolerance test (ITT)were performed in all the mice.After the establishment of IR model,the mice of HFD-T group were injected intraperitoneally with TLR4 inhibitor TAK-242 twice a week for five consecutive months.All the mice were sacrificed and their serum and aortic artery tissue samples were collected after underwent GTT and ITT by the end of the treatments.The expressions of TLR4,tumor necrosis factor α (TNF-α)and interleukin-6(IL-6)in aortic artery tissue were determined using real-time quantitative PCR(RT-PCR).Automatic biochemical analyzer was used to detect serum total cholesterol(TC),high-density lipoprotein cholesterol (HDL-C),low-density lipoprotein cholesterol (LDL-C),and triglyceride (TG)levels.Results Compared with the mice of LFD group,those of HFD group showed significantly higher body weight (30.05±1.67 vs.28.29±1.30 grams,P<0.05),impaired glucose regulation,and decreased insulin sensitivity seven months after the treatment;five months after the TAK-242 intervention,the glucose tolerance and insulin sensitivity of HFD-T group were improved compared with those of the HFD-C group.The serum TG,TC,LDL-C,and HDL-C were significantly increased in the mice of HFD-T and HFD-C group compared to those in the mice of LFD (P<0.05 for all);however,there were no significant differences in serum TG,TC,LDL-C,and HDL-C between HFD-T and HFD-C group.RT-PCR results revealed significantly higher expressions of TLR4 (1.91±0.32 vs.1.00±0.20),TNF-α (2.71±0.52 vs.1.00±0.17),and IL-6 (3.24±0.41 vs.1.00±0.23) in aortic artery tissues of HFD-C group compared to those of the LFD group (P<0.01 for all) and down-regulated expressions of TLR4 (1.23±0.27),TNF-α (1.93±0.35),and IL-6 (1.67±0.30) in aortic artery tissues of HFD-T group compared with those of HFD-C group.Conclusion High fat diet could induce insulin resistance in mice.The inflammatory reaction of aortic artery may be associated with the activation of TLR4 signaling pathway in mice with insulin resistance.