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Regulation of Agouti-Related Protein Messenger Ribonucleic Acid Transcription and Peptide Secretion by Acute and Chronic Inflammation

Center for the Study of Weight Regulation and Associated Disorders L481 (J.M.S., X.Z., D.D.B., A.K.B., P.R.L., W.F.G., D.L.M.), and Department of Pediatrics (D.L.M.), Oregon Health & Science University Child Development and Rehabilitation Center Portland, Portland, Oregon 97239; Division of Neuroscience (P.J.E., M.A.C.), Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006; and Surgical Metabolism and Nutrition Laboratory (M.M.M.), Department Surgery, State University of New York Upstate Medical University, Syracuse, New York 13210

Address all correspondence and requests for reprints to: Daniel L. Marks, M.D., Ph.D., Center for the Study of Weight Regulation, Oregon Health & Science University, Mail code L-481, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239. E-mail: marksd{at}ohsu.edu.

Agouti-related protein (AgRP) is an orexigenic neuropeptide produced by neurons in the hypothalamic arcuate nucleus (ARC) that is a key component of central neural circuits that control food intake and energy expenditure. Disorders in energy homeostasis, characterized by hypophagia and increased metabolic rate, frequently develop in animals with either acute or chronic diseases. Recently, studies have demonstrated that proopiomelanocortin-expressing neurons in the ARC are activated by the proinflammatory cytokine IL-1β. In the current study, we sought to determine whether inflammatory processes regulate the expression of AgRP mRNA and to characterize the response of AgRP neurons to IL-1β. Here, we show by real-time RT-PCR and in situ hybridization analysis that AgRP mRNA expression in rodents is increased in models of acute and chronic inflammation. AgRP neurons were found to express the type I IL-1 receptor, and the percentage of expression was significantly increased after peripheral administration of lipopolysaccharide. Furthermore, we demonstrate that IL-1β inhibits the release of AgRP from hypothalamic explants. Collectively, these data indicate that proinflammatory signals decrease the secretion of AgRP while increasing the transcription of the AgRP gene. These observations suggest that AgRP neurons may participate with ARC proopiomelanocortin neurons in mediating the anorexic and metabolic responses to acute and chronic disease processes.