Effects Of FGF-21 Gene Knockdown On Glucose And Lipid Metabolism In APOE^-/- Mice

Objective To investigate the in vivo effects of down-regulating the FGF-21 gene expression by shRNA on glucose and lipids metabolism in high fat diet fed ApoE-/- mice (HFD).Methods Male 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 + 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 week. The insulin sensitivity and glucose-lipid metabolism were assessed by the hyperinsulinemic- euglycemic clamp technique using 3-[3H] glucose as a tracer at the end of 16 week.Results The plasma FGF-21 levels in NFG and HFG groups were significantly degraded than that in NF and HF group (20%,27%, P<0.05), respectively. In the basal state, the fasting blood glucose (FBG), fasting plasma insulin (PIns), free fatty acids (FFA), TG, TC 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 that in NF and HF groups (P<0.05 or 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 (P<0.05 or 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).Conclusion FGF-21 knockdown aggravated the gluco-lipid metabolism disorder in ApoE-/- knock out mice.