Abstract： Objective To explore the effect of high-fat diet on IRS-1 and IRS-2 expressions of fatty liver in rat. Methods After the rats were fed a high-fat diet (n=7) and a standard chow(n=7) for 8 weeks, insulin sensitivity,lipid metabolism, TNF-α and hepatic mRNA and protein expressions of IRS-1 and IRS-2 were measured. Results Compared with the normal control, the high-fat diet group displayed the elevated levels of insulin resistance,FFA and TNF-α.Hepatic IRS-1 mRNA expression and IRS-1 protein content were reduced by 28% and 32%(P<0.01),respectively. Similarly, hepatic IRS-2 mRNA and IRS-2 protein content were also reduced by 30% and 27% (P<0.01), respectively. Conclusions High-fat diet results in a significant decrease in expressions of mRNA and protein of hepatic IRS-1 and IRS-2 in rats, which might be one of the molecular mechanisms of insulin resistance in liver steatosis induced by high-fat diet