Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice

Obesity is a major health care problem and is associated with significant c ardiovascular morbidity. Leptin, a neuroendocrine hormone released by adipo se tissue, is important in modulating obesity by signaling satiety and incr easing metabolism. Moreover, leptin receptors are expressed on vascular end othelial cells (ECs) and mediate angiogenesis. We hypothesized that leptin may also play an important role in vasoregulation. We investigated vasoregu latory mechanisms in the leptin-deficient obese (ob/ob) mouse model and det ermined the influence of leptin replacement on endothelial-dependent vasore laxant responses. The direct effect of leptin on EC nitric oxide (NO) produ ction was also tested by using 4,5-diaminofluorescein-2 diacetate staining and measurement of nitrate and nitrite concentrations. Vasoconstrictor resp onses to phenylepkrine, norepinephrine, and U-46619 were markedly enhanced in aortic rings from ob/ob mice and were modulated by NO synthase inhibitio n. Vasorelaxant responses to ACh were markedly attenuated in mesenteric mic rovessels from ob/ob mice. Leptin replacement resulted in significant weigh t loss and reversal of the impaired endothelial-dependent vasorelaxant resp onses observed in ob/ob mice. Preincubation of ECs with leptin enhanced the release of NO production. Thus leptin-deficient ob/ob mice demonstrate mar ked abnormalities in vasoregulation, including impaired endothelial-depende nt vasodilation, which is reversed by leptin replacement. These findings ma y be partially explained by the direct effect of leptin on endothelial NO p roduction. These vascular abnormalities are similar to those observed in ob ese, diabetic, leptin-resistant humans. The ob/ob mouse may, therefore, be an excellent new model for the study of the cardiovascular effects of obesi ty.