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Regulation of Central Melanocortin Signaling by Interleukin-1ß

Center for the Study of Weight Regulation and Associated Disorders (J.M.S., D.D.B., A.K.B., W.F.G., D.L.M.) and Department of Pediatrics (D.L.M.), Child Development and Rehabilitation Center, Oregon Health and Science University, Portland, Oregon 97239; Division of Neuroscience (E.E.J., P.J.E., M.A.C.), Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006; and School of Physical Therapy (E.E.J.), Pacific University, Hillsboro, Oregon 97123

Address all correspondence and requests for reprints to: Daniel L. Marks, M.D., Ph.D., Center for the Study of Weight Regulation and Associated Disorders, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239. E-mail: marksd{at}ohsu.edu; or Michael A. Cowley, Ph.D., Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon 97006. E-mail: cowleym{at}ohsu.edu.

Anorexia and involuntary weight loss are common and debilitating complications of a number of chronic diseases and inflammatory states. Proinflammatory cytokines, including IL-1ß, are hypothesized to mediate these responses through direct actions on the central nervous system. However, the neural circuits through which proinflammatory cytokines regulate food intake and energy balance remain to be characterized. Here we report that IL-1ß activates the central melanocortin system, a key neuronal circuit in the regulation of energy homeostasis. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) were found to express the type I IL-1 receptor. Intracerebroventricular injection of IL-1ß induced the expression of Fos protein in ARC POMC neurons but not in POMC neurons in the commissural nucleus of the tractus solitarius. We further show that IL-1ß increases the frequency of action potentials of ARC POMC neurons and stimulates the release of -MSH from hypothalamic explants in a dose-dependent fashion. Collectively, our data support a model in which IL-1ß increases central melanocortin signaling by activating a subpopulation of hypothalamic POMC neurons and stimulating their release of -MSH.

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