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Leptin Modulates Orexigenic Effects of Ghrelin and Attenuates Adiponectin and Insulin Levels and Selectively the Dark-Phase Feeding as Revealed by Central Leptin Gene Therapy

Department of Neuroscience (N.U., S.P.K.), University of Florida McKnight Brain Institute, College of Medicine, Gainesville, Florida 32610-0244 Department of Physiology and Functional Genomics (M.G.D., P.S.K.), Gainesville, Florida 32610-0274; and Division of Diabetes, Digestive, and Kidney Diseases (N.U., A.I.), Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Address all correspondence and requests for reprints to: Satya P. Kalra, Ph.D., Department of Neuroscience, McKnight Brain Institute, P.O. Box 100244, Gainesville, Florida 32610-0244. E-mail: skalra{at}mbi.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 (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, TNF, 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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