The effect of RNA interference-mediated adiponectin gene silence on glucose-lipid metabolism in apolipoprotein E gene knock-out(ApoE~(-/-)) mice was studied. The plasma adiponectin level in ApoE~(-/-) mice with high-fat diet and adiponectin short hairpin RNA (shRNA) adenovirus injection (ADI group) was significantly lower than that in ApoE~(-/-)mice with high-fat diet(HF group), normal-chow(NF group)and naked adenovirus injection (GF, both P<0.01). Fasting blood glucose, fasting plasma insulin, free fatty acids, total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and body weight were significandy elevated in three high-fat diet groups compared with in NF group, (P<0.01). However, fasting plasma insulin, free fatty acids, total cholesterol, triglycerides, LDL-C, and HDL-C in ADI group were significantly higher than those in HF and GF groups(P<0.01 or P<0. 05). A typical clinical phenotype of glucose-lipid metabolism and insulin resistance in ApoE~(-/-) mice can be induced by high-fat feeding and adiponecting gene silencing.