Abstract: AIM To investigate the effect of branched chain amino acids (BCAA) on high-fat-induced insulin resistance. METHODSSixty wild-type C57BL/6J mice were randomly divided into four groups and were offered a choice of normal diets with tap water (ND group), normal diets with tap water containing 50 g/L BCAA (ND/BCAA group), high-fat diets (HD group), and high-fat diets with tap water containing 50 g/L BCAA (HD/BCAA group) for 18 weeks. Status of mice in each group was carefully observed and body weight was recorded every week. We then performed glucose and insulin tolerance tests, detected the serum level of BCAA and insulin in mice, and detected liver insulin signaling key molecules IRS1 and its phosphorylation level ［p-IRS1(ser307)］, AKT and its phosphorylation level ［p-AKT(ser473)］ by Western blot. RESULTSBCAA supplementation inhibited body weight gain induced by high-fat diets, and body weight gain in the HD/BCAA group was significantly lower compared with HD group (P<0.05, P<0.01). Body weight gain between ND group and ND/BCAA group was not significantly different. Compared with the ND group, serum BCAA concentration in the ND/BCAA group was not significantly increased, whereas the serum level of BCAA in HD group was significantly higher (P<0.05) and the BCAA level in HD/BCAA group increased further (P<0.05) compared with HD group. Compared with ND group, serum insulin level, glucose and insulin tolerances in ND/BCAA group were not significantly different. HD/BCAA group showed a higher serum insulin level, impaired glucose and insulin tolerance compared with HD group (P<0.05). Western blot showed that p-IRS1 (ser307) and p-AKT (ser473) levels were not significantly different between ND group and ND/BCAA group. When compared with ND group, HD group showed up-regulated p-IRS1 (ser307) (P<0.05) and down-regulated IRS1 and p-AKT (ser473) (P<0.05, P<0.01). HD/BCAA group showed a further up-regulated p-IRS1 (ser307) (P<0.05) and more down-regulated p-AKT (ser473) (P<0.01) when compared with HD group. CONCLUSIONNormal diets supplemented with BCAA did not affect liver insulin sensitivity in mice, but BCAA facilitates high-fat-induced insulin resistance in the liver.