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Role of the Central Melanocortin Circuitry in Adaptive Thermogenesis of Brown Adipose Tissue

Center for the Study of Weight Regulation and Associated Disorders (A.V.-A., J.G.M., K.L.J.E., R.D.C., W.F.) and Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239; and Division of Endocrinology (R.C.S., E.A.N.), Brown Medical School/Rhode Island Hospital, Providence, Rhode Island 02903

Address all correspondence and requests for reprints to: Roger D. Cone or Wei Fan, Center for the Study of Weight Regulation and Associated Disorders and Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239-3098. E-mail: cone{at}ohsu.edu or fanw{at}ohsu.edu.

The central melanocortin 4 receptor (MC4R) plays a critical role in energy homeostasis, although little is known regarding its role in the regulation of adaptive thermogenesis of brown adipose tissue (BAT). Here we show using retrograde transsynaptic tracing with attenuated pseudorabies virus coupled with dual-label immunohistochemistry that specific subsets of MC4R-expressing neurons in multiple nuclei of the central nervous system known to regulate sympathetic outflow polysynaptically connect with interscapular BAT (IBAT). Furthermore, we show that MC4R^–/– and agouti-related peptide-treated mice are defective in HF diet-induced up-regulation of uncoupling protein 1 in IBAT. Additionally, MC4R^–/– mice exposed to 4 C for 4 h exhibit a defect in up-regulation of uncoupling protein 1 levels in IBAT. Our results provide a neuroanatomic substrate for MC4R regulating sympathetically mediated IBAT thermogenesis and demonstrate that the MC4R is critically required for acute high-fat- and cold-induced IBAT thermogenesis.

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