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Submitted on March 1, 2004
Accepted on May 11, 2004
University of Florida McKnight Brain Institute, College of Medicine, Departments of Neuroscience, PO Box 100244, Gainesville, FL, 32610-0244, Physiology & Functional Genomics, PO Box 100274, Gainesville, FL 32610-0274, USA and Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
* To whom correspondence should be addressed. E-mail: skalra{at}ufbi.ufl.edu.
We tested the hypothesis that leptin acts centrally and peripherally by different mechanisms to control peripheral hormones that normally regulate weight homeostasis. The paradigm of selectively increasing leptin transgene expression with a single intracerebroventricular injection of adeno-associated viral vectors encoding leptin (rAAV-lep) or green fluorescent protein (rAAV-GFP, control) in the hypothalamus of mutant leptin-deficient ob/ob and wild-type (wt) mice was employed in these experiments. rAAV-lep injection increased hypothalamic leptin expression in the complete absence of peripheral leptin in ob/ob mice, suppressed body weight and adiposity, voluntarily decreased dark-phase food intake, suppressed plasma levels of adiponectin, transforming tumor necrosis factor, free fatty acids and insulin, concomitant with normoglycemia, and elevated ghrelin levels for extended period. Body weight and plasma levels of leptin and metabolic variables were suppressed to a lesser extent in rAAV-lep wt mice without decreasing food intake. The sustained high leptin transgene expression decreased only the dark-phase phagia in both genotypes but wt mice escaped from leptin restraint during the lights-on phase resulting in normal overall food intake. Leptin administration rapidly decreased plasma gastric ghrelin and adipocyte adiponectin but not TNF
levels thereby demonstrating a peripheral restraining action of leptin on the secretion of hormones of varied origins. Whereas ghrelin administration readily stimulated feeding in controls it was completely ineffective in rAAV-lep treated wt mice. Thus, leptin expressed locally in the hypothalamus counteracted the central orexigenic effects of peripheral ghrelin. Cumulatively, these results identify newer central and peripheral modulatory influences of leptin on hormonal signals of disparate origin implicated in weight homeostasis and metabolic disorders.
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insulin •
obesity •
gene therapy
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