{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe melanocortin‐4 receptor (MC4R) is a central regulator of energy homeostasis whose proper function in the central nervous system is essential for the long‐term maintenance of body weight. Genetic studies have repeatedly shown that both rare loss‐of‐function mutations and common variants in or near MC4R are strongly associated with increased body mass index, adiposity, waist circumference, and even insulin resistance. In fact, mutations in MC4R represent the most common form of monogenic obesity in both children and adults, and common alleles may modulate appetite and feeding behavior through neural pathways, underscoring the critical role of the central nervous system in obesity predisposition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOn the molecular level, MC4R is a G protein–coupled receptor (GPCR) expressed predominantly in hypothalamic neurons where it mediates the anorexigenic effects of pro‐opiomelanocortin (POMC)–derived peptides such as alpha-melanocyte stimulating hormone (α-MSH). Its activity is finely tuned by both endogenous agonists and the competitive antagonist agouti-related protein (AGRP), and it even exhibits intrinsic constitutive signaling maintained by a tethered intramolecular ligand. Functional analyses of various MC4R mutations have revealed that many impair ligand binding and signal transduction by causing misfolding or intracellular retention of the receptor; additionally, recent work indicates that proper localization of MC4R to the primary cilia of hypothalamic neurons—where it colocalizes with adenylyl cyclase 3—is vital for its normal function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, both pathogenic and protective MC4R variants have been characterized. While many mutations that disrupt receptor expression or function lead to early-onset, severe obesity by impairing satiety signals, some common alleles (such as V103I and I251L) appear to confer a modest protective effect against obesity. Moreover, MC4R variants are not only linked to altered energy intake and increased adiposity but also, in some studies, to downstream metabolic disturbances such as insulin resistance and type 2 diabetes. Together, these findings highlight MC4R’s central role in translating central melanocortin signals into peripheral energy balance outcomes and suggest that targeted modulation of MC4R activity could represent a promising therapeutic strategy against obesity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Cristen J Willer, Elizabeth K Speliotes, Ruth J F Loos, et al. 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