{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe melanocortin‐3 receptor (MC3R) is a G protein–coupled receptor that plays a central role in energy homeostasis. Multiple studies in both animal models and humans have demonstrated that MC3R critically influences body weight regulation by modulating feeding efficiency, nutrient partitioning, and adipose tissue deposition. In several investigations, loss‐of‐function mutations (such as I183N) or combinations of naturally occurring variants were linked to increased fat mass, higher insulin and leptin levels, and altered body composition, thereby predisposing to obesity even in the absence of significant hyperphagia. These findings underscore the receptor’s importance in orchestrating the balance between calorie intake and nutrient allocation during growth and development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, MC3R mediates its actions primarily through canonical cyclic AMP (cAMP) signaling as well as through alternative pathways such as the extracellular signal–regulated kinase (ERK1/2) cascade. Detailed structure–function studies using site‐directed mutagenesis have mapped key residues in transmembrane domains—including acidic residues and motifs critical for receptor activation—and have revealed that certain mutations cause impaired ligand binding, receptor trafficking, or even biased agonism. In addition, the receptor can form homo‐ and heterodimers with other family members, a property that may further modulate its downstream signaling and regulatory functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in energy balance, emerging evidence indicates that MC3R is involved in developmental processes such as the timing of sexual maturation, linear growth, and the accrual of lean mass. Human genetic studies—including knock‐in mouse models carrying double mutations—have revealed that impaired MC3R signaling may lead not only to increased adiposity but also to altered nutrient partitioning into metabolically “healthy” fat accumulation. Furthermore, the receptor exhibits complex ligand–dependent behavior, including endocytosis and differential (or biased) activation of intracellular kinases, suggesting that MC3R signaling may be fine‐tuned to regulate diverse physiological outcomes. These findings collectively illuminate the multifaceted contributions of MC3R to metabolic control and developmental regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yung-Seng Lee, Larry Kok-Seng Poh, Kah-Yin Loke "}, {"type": "b", "children": [{"type": "t", "text": "A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jcem.87.3.8461"}], "href": "https://doi.org/10.1210/jcem.87.3.8461"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11889220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11889220"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Andreas Breit, Katharina Wolff, Hermann Kalwa, et al. 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