Abstract: OBJECTIVE To investigate the effects of aspirin on insulin sensitivity and Mfn2 mRNA expression in rats fed with high-fat diet. METHODS Twenty-four male rats were randomly divided into normal control diet group (NC, n=8), high-fat diet group (HF, n=8) and aspirin group (AF, n=8) according to random digits table. After treatment with different diets for 8 weeks, insulin sensitivity was evaluated by measuring the glucose infusion rate (GIR) using a hyperinsulinemic euglycemic clamp. The levels of serum alanine aminotransferase (ALT), aspartate transaminase (AST), triglycerides(TG), fasting blood sugar(FBS) and insulin(FINS) were measured respectively. The liver tissues of three groups were fixed, sliced, stained and observed with light microscope. The liver glycogen was determined. Superoxide dismutase (SOD) in liver mitochondria was extrated and measured. Mfn2 mRNA in hepatic tissue was detected by reverse transcription PCR. RESULTS Compared with the NC group, the liver index and the levels of serum TG, FBS, ALT, AST, and insulin in the HF group were statistically increased (P<0.05). The GIR, SOD, and expression of Mfn2 mRNA in the HF group were significantly decreased (P<0.05). However, there was no difference in above indicators between the NC group and the AF group. Pathological change of liver tissues by HE staining, normal hepatic plates were shown in NC and AF groups. In HF group, the liver cells of rats showed an increase in size, and included the storage of lipid droplets. CONCLUSION Aspirin can improve insulin sensitivity and inhibit hepatic steatosis by high-fat induced, may be partly attributable to promote expression of Mfn2 and improve mitochondrial function in liver of rats.