ObjectiveTo investigate the in vivo effects of down-regulating the FGF-21 gene expression by shRNA on glucose and lipids metabolism in high fat diet (HFD) fed ApoE-/- mice.MethoedsMale ApoE-/- mice were randomly divided into chow diet (CF)fed group ( NF,n =10),CF fed + pAd-shFGF-21 group ( NFG,n =9),and HFD fed group ( HF,n =10),HFD fed + Adv-null vector ( pAd-GFP ) group ( GFP,n =6) and HFD fed + pAd-shFGF-21 group ( HFG,n =10).Mice were fed for 16 weeks.C57BL/6J mice were set as control group ( NC group,n=10).NFG,HFG,and GFP groups were injected with pAd-shFGF-21or pAd-GFP by tail vein at the end of 15 weeks.The insulin sensitivity and glucoselipid metabolism were assessed by the hyperinsulinemic- euglycemic clamp technique using 3-[ 3 H] glucose as a tracer at the end of 16 week.ResultsThe plasma FGF-21 levels in NFG and HFG groups were significantly degraded than those in NF and HF groups(20％-27％,P＜0.05),respectively.In the basal state,the fasting blood glucose,fasting plasma insulin,free fatty-acids,triglycerides,total cholesterol,and LDL-C were significantly higher,while the HDL-C was lower in NFG and HFG groups compared with those in NF and HF groups,respectively (P＜0.05 or P＜0.01 ).During the steady-state of clamp,FFA was suppressed in all groups,but it was still higher in NFG and HFG groups than NF and HF groups ( P＜0.05or P＜0.01 ).The glucose infusion rate (GIR)and glucose disappearance rate (GRd)in NFG and HFG groups were significantly decreased compared with NF and HF groups (all P＜0.01 ).In addition,insulin's ability to suppress hepatic glucose production (HGP) during clamps was significantly decreased in HFG and NFG group compared with HF and NF groups (49％ and 20％,respectively; all P＜0.01 ).ConclusionFGF-21 knockdown and low FGF-21 level facilitate the development of metabolic disorder and insulin resistance.