PURPOSE: Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, is an antidiabetic drug. It has been shown to improve endothelial dysfunction, but the mechanism remains somewhat unclear. Leptin can also improve endothelial function. Cardiovascular disease (CVD) is linked to hyperleptinemia, and leptin resistance, how liraglutide influences the effect of leptin on endothelial function, is never reported. We used palmitic acid (PA) to mimic hyperlipidemia in endothelial cells to explore the cardio-protective mechanism of liraglutide and its impact on the role of leptin. METHODS: Human umbilical vein endothelial cells (HUVECs) were incubated with PA for 16 h and then were treated with liraglutide for 30 min. RESULTS: PA elevated not only phosphorylation of JNK and IKK alpha/beta, but also the expression of IL-6 in HUVECs. These effects of PA were reversed by liraglutide. In addition, liraglutide increased phosphorylation of eNOS, AMPK, and the release of NO but had no effect on PKC phosphorylation. In addition, leptin elevated eNOS phosphorylation but was abrogated by PA. However, in the presence of liraglutide, leptin regained its function of elevating eNOS phosphorylation. Last, we found that liraglutide inhibited PA elevated SOCS3, which is a marker of leptin resistance. CONCLUSIONS: GLP-1 impairs endothelial inflammatory signals, improves endothelial function, and reverses leptin resistance. (C) 2016 Elsevier Inc. All rights reserved.