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The MC system is a family of five G protein-coupled receptors, melanocortin-1 through -5 receptors (MC1R-MC5R), that play an integral role in neuroendocrine signaling ( Figure 1 , particularly in centers of metabolic control including the arcuate nucleus (ARC), paraventricular nucleus (PVN), nucleus of the solitary tract (NTS), and paraventricular thalamus (PVT) ( Figure 1 The melanocortin receptors are modulated by several endogenous peptides, such as -, -, and -melanocyte stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH), which are derived from proopiomelanocortin (POMC) precursors ( Early prioritization of MC4R as a therapeutic target for obesity was driven by converging genetic and pharmacological evidence demonstrating its primary role in regulating food intake and body weight

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