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Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) miceObesity is a major health care problem and is associated with significant cardiovascular morbidity. Leptin, a neuroendocrine hormone released by adipose tissue, is important in modulating obesity by signaling satiety and increasing metabolism. Moreover, leptin receptors are expressed on vascular endothelial cells (ECs) and mediate angiogenesis. We hypothesized that leptin may also play an important role in vasoregulation. We investigated vasoregulatory mechanisms in the leptin-deficient obese (ob/ob) mouse model and determined the influence of leptin replacement on endothelial-dependent vasorelaxant responses. The direct effect of leptin on EC nitric oxide (NO) production was also tested by using 4, 5-diaminofluorescein-2 diacetate staining and measurement of nitrate and nitrite concentrations. Vasoconstrictor responses to phenylephrine, norepinephrine, and U-46619 were markedly enhanced in aortic rings from ob/ob mice and were modulated by NO synthase inhibition. Vasorelaxant responses to ACh were markedly attenuated in mesenteric microvessels from ob/ob mice. Leptin replacement resulted in significant weight loss and reversal of the impaired endothelial-dependent vasorelaxant responses observed in ob/ob mice. Preincubation of ECs with leptin enhanced the release of NO production. Thus leptin-deficient ob/ob mice demonstrate marked abnormalities in vasoregulation, including impaired endothelial-dependent vasodilation, which is reversed by leptin replacement. These findings may be partially explained by the direct effect of leptin on endothelial NO production. These vascular abnormalities are similar to those observed in obese, diabetic, leptin-resistant humans. The ob/ob mouse may, therefore, be an excellent new model for the study of the cardiovascular effects of obesity.
Document ID
20040112677
Acquisition Source
Legacy CDMS
Document Type
Reprint (Version printed in journal)
Authors
Winters, B.
(Johns Hopkins University School of Medicine Baltimore, Maryland 21287, United States)
Mo, Z.
Brooks-Asplund, E.
Kim, S.
Shoukas, A.
Li, D.
Nyhan, D.
Berkowitz, D. E.
Date Acquired
August 21, 2013
Publication Date
December 1, 2000
Publication Information
Publication: Journal of applied physiology (Bethesda, Md. : 1985)
Volume: 89
Issue: 6
ISSN: 8750-7587
Subject Category
Life Sciences (General)
Distribution Limits
Public
Copyright
Other
Keywords
NASA Program Biomedical Research and Countermeasures
Non-NASA Center
NASA Discipline Cardiopulmonary

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