Objective To investigate the effects of liraglutide on glucose-lipid metabolism in ApoE-/-mice with RNAi-mediated adiponectin gene inhibition. Methods The dose-effective relationship of liraglutide was evaluated by intravenous glucose tolerance test (IVGTT), and the insulin sensitivity and glucose-lipid metabolism were assessed by the hyperinsulinemic-euglycemic clamp technique using 3-[3 H]-glucose as a tracer. Results In the IVGTT, blood glucose was significantly lower in the 1 mg/kg liraglutide group than that in other groups ( all P＜0. 01 ) at the points of 5, 15, and 30 min after glucose load. However, plasma insulin was significantly higher at the points of 5 and 15 min (all P＜0. 01 ). Fasting blood glucose (FBG), body weight, free fatty acids (FFA),total cholesterol, triglycerides, low-density lipoprotein-cholesterol ( LDL-C), and fasting plasma insulin in ApoE-/-mice with co-injection of liraglutide and adiponectin shRNA adenovirus ( HEA group ) were significantly lower than those in ApoE-/-mice with adiponectin shRNA adenovirus injection ( ADI group, P＜0. 05 or P＜0. 01 ). However,high-density lipoprotein-cholesterol (HDL-C) was significantly higher than the latter (P＜0. 05 ). During the steady-state of clamp, plasma insulin in ADI group was significantly higher than that in HEA group (P＜0. 01 ). Although FFA, total cholesterol, and triglycerides were suppressed in all groups, they were still higher in ADI group than those in HEA group (P＜0. 05). Glucose infusion rate (GIR) in HEA group were significantly higher than that in ADI group ( P ＜ 0. 01 ). At the end of clamp, glucose disappearance rate ( GRd ) was significantly lower, and hepatic glucose production significantly higher in ADI group than those in HEA group (P＜0.01 ). Conclusion Administration of liraglutide may ameliorate insulin resistance via increasing plasma adiponectin level in ApoE-/-mice with RNAi-mediated adiponectin gene inhibition.