Leptin Stimulates Both Endothelin-1 and Nitric Oxide Activity in Lean Subjects But Not in Patients With Obesity-Related Metabolic Syndrome

Context: Leptin has nitric oxide (NO)-dependent vasodilator actions, but hyperleptinemia is an independent risk factor for cardiovascular disease. Objective: The objective of the study was to investigate whether, in the human circulation, properties of leptin to release NO are opposed by stimulation of vasculotoxic substances, such as endothelin (ET)-1, and whether this mechanism might contribute to vascular damage in hyperleptinemic states like obesity. Methods: Forearm blood flow responses (plethysmography) to ETA receptor antagonism (BQ-123, 10 nmol/min) and NO synthase inhibition [N-G-monomethyl L-arginine (L-NMMA), 4 mu mol/min] were assessed before and after intraarterial administration of leptin (2 mu g/min) in lean controls (n = 8) and patients with obesity-related metabolic syndrome (MetS; n = 8). Results: Baseline plasma leptin was higher in patients than in controls (P < .001). Before infusion of leptin, the vasodilator response to BQ-123 was greater in patients than in controls (P < .001), whereas infusion of L-NMMA induced higher vasoconstriction in controls than in patients (P = .04). In lean subjects, hyperleptinemia resulted in increased vasodilator response to ETA receptor antagonism (P < .001 vs before) and enhanced vasoconstrictor effect of L-NMMA during ETA receptor blockade (P = .015 vs before). In patients with the MetS, by contrast, vascular responses to both BQ-123 and L-NMMA were not modified by exogenous leptin (both P > .05 vs before). Conclusions: These findings indicate that, under physiological conditions, leptin stimulates both ET-1 and NO activity in the human circulation. This effect is absent in hyperleptinemic patients with the MetS who are unresponsive to additional leptin. In these patients, therefore, hyperleptinemia may be a biomarker of vascular dysfunction, rather than a mediator of vascular damage. (J Clin Endocrinol Metab 98: 1235-1241, 2013)