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Growing evidence suggests that hepatic-insulin resistance is sufficient to promote progression to cardiovascular disease. We have shown previously that liver-specific protein-tyrosine-phosphatase 1B (PTP1B) deficiency improves hepatic-insulin sensitivity and whole-body glucose homeostasis. The aim of this study was to investigate the impact of liver-specific PTP1B-deficiency (L-PTP1B−/−) on cardiac and peripheral vascular function, with special emphasis on endothelial function in the context of high-fat diet (HFD)-induced obesity.L-PTP1B−/− mice exhibited an improved glucose and lipid homeostasis and increased insulin sensitivity, without changes in body weight. HFD-feeding increased systolic blood pressure (BP) in both L-PTP1B−/− and control littermates; however, this was significantly lower in L-PTP1B−/− mice. HFD-feeding increased diastolic BP in control mice only, whilst the L-PTP1B−/− mice were completely protected. The analysis of the function of the left ventricle (LV) revealed that HFD-feeding decreased LV fractional shortening in control animals, which was not observed in L-PTP1B−/− mice. Importantly, HFD feeding significantly impaired endothelium-dependent vasorelaxation in response to acetylcholine in aortas from control mice, whilst L-PTP1B−/− mice were fully protected. This was associated with alterations in eNOS phosphorylation. Selective inhibition of COX-2, using NS-398, decreased the contractile response in response to serotonin (5-HT) only in vessels from control mice. HFD-fed control mice released enhanced levels of prostaglandin E, a vasoconstrictor metabolite; whilst both chow- and HFD-fed L-PTP1B−/− mice released higher levels of prostacylin, a vasorelaxant metabolite.Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects.