Vascular Effects of Obestatin in Lean and Obese Subjects.

Abstract

Obese patients have impaired vasodilator reactivity and increased endothelin 1 (ET-1)-mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)-dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1-dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating doses of obestatin resulted in a progressive increase in blood flow from baseline (both <i>P</i> < 0.001). This vasodilation was predominantly mediated by enhanced NO activity, because <i>N</i>^G-monomethyl-l-arginine markedly blunted the flow response to obestatin in both groups (both <i>P</i> < 0.05 vs. saline). In obese subjects, antagonism of ET_A receptors by BQ-123 increased forearm flow during saline (<i>P</i> < 0.001) but did not induce additional vasodilation (<i>P</i> > 0.05) during obestatin. Circulating obestatin levels were not different between lean and obese participants (<i>P</i> = 0.41). Our findings indicate that obestatin causes NO-dependent vasodilation in the human circulation. This effect is preserved in obesity, where it is accompanied by reduced ET-1-mediated vasoconstriction. These latter observations make obestatin a promising target for vascular prevention in obesity and diabetes.