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Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake

Graduate Groups of Psychology and Neuroscience (H.J.G., J.M.K., J.S.F., D.G.B), University of Pennsylvania, Philadelphia, Pennsylvania 19104; and Veterans Affairs, Puget Sound Health Care System (D.G.B.), Seattle, Washington 98108, and Departments of Medicine (M.W.S., J.B., D.G.B.) and Biological Structure (D.G.B.), University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: Harvey Grill, University of Pennsylvania, Department of Psychology, 3815 Walnut Street, Philadelphia, Pennsylvania 19104. E-mail: grill{at}psych.upenn.edu

Three experiments were performed to investigate the hypothesis that leptin action within the caudal brain stem (CBS) contributes to its intake inhibitory effects. The first experiment evaluated the anatomical distribution of leptin receptor mRNA in rat CBS using a sensitive fluorescence in situ hybridization method with a riboprobe specific for the long form of the leptin receptor (Ob-Rb). An Ob-Rb mRNA hybridization signal was detected in neurons of several CBS nuclei involved in the control of food intake, including the dorsal vagal complex and parabrachial nucleus. A strong hybridization signal was also obtained from neuronal cell bodies of a number of other structures including the hypoglossal, trigeminal, lateral reticular, and cochlear nuclei; locus ceruleus; and inferior olive. The anatomical profile revealed by fluorescence in situ hybridization was in good agreement with immunocytochemical analysis with an antibody specific to Ob-Rb. In a second experiment, exploring the relevance of CBS Ob-Rb to feeding behavior, rats were given a fourth intracerebroventricular (i.c.v.) injection of leptin (0.1, 0.83, or 5.0 µg; n = 9–11/group) or vehicle 30 min before lights-out on three consecutive days The two higher doses reduced food intake significantly at 2, 4, and 24 h after injection and caused significant reductions of body weight. The dose-response profiles for fourth i.c.v. administration were indistinguishable from those obtained from separate groups of rats that received leptin via a lateral i.c.v. cannula. In the last experiment, a ventricle-subthreshold dose of leptin (0.1 µg) microinjected unilaterally into the dorsal vagal complex suppressed food intake at 2, 4, and 24 h. The results indicate that the CBS contains neurons that are potentially direct targets for the action of leptin in the control of energy homeostasis.