Abstract: Objective To investigate the effect of leucine on fat mass and leptin resistance in mice fed with a high-fat/cholesterol (HFC) diet.Methods Sixty male C57BL/6J mice were randomly divided into four groups:control group,high fat/cholesterol diet group,low and high leucine (1.5% and 3.0%) groups and treated for 24 weeks.Body weight,fat mass,serum levels of cholesterol and leptin were measured.Protein expression of leptin receptor (Ob-R),Janus protein tyrosine kinase 2 (JAK2),signal transducers and activators of transcription 3 (STAT3),and suppressors of cytokine signaling 3 (SOCS3) in epididymal adipose tissue were analyzed with Western blot.Results The body weight,fat weight,and serum cholesterol level in the mice of high fat/cholesterol diet group increased,while those in the mice of leucine group decreased significantly.Serum leptin level was significant higher in the mice of high fat/cholesterol diet group than in those of the control group (7.14±2.44 vs.0.73±0.42 ng/ml,P<0.01).For the mice of leucine groups,the serum leptin level was deceased (4.21±2.37 and 4.24±2.22 ng/ml) and Ob-R,JAK2 expressions were upregulated,whereas the STAT3 expression was downregulated compared with the mice of high fat/cholestrol diet group.Conclusion Leucine supplementation can suppress weight gain and fat mass in the mice fed with high fat/cholesterol diet probably by regulating the expressions of JAK2 and SOCS3 and improving leptin resistance.