MC4R

MC4R (melanocortin-4 receptor) is a class A G protein-coupled receptor that functions as a central regulator of appetite, energy expenditure, and body-weight homeostasis within the hypothalamic leptin-melanocortin network^[1][2]. Activation of proopiomelanocortin (POMC) neurons promotes release of α-melanocyte-stimulating hormone (α-MSH), which activates MC4R signaling and suppresses food intake while increasing energy expenditure, establishing MC4R as a key effector of energy balance regulation^[3][1]. Mechanistically, MC4R integrates neuroendocrine signals controlling satiety and metabolic homeostasis, and disruption of MC4R signaling impairs these regulatory processes^[2][4]. Disease relevance is strongly supported by human genetics, as MC4R deficiency represents the most common monogenic cause of obesity, and loss-of-function variants are associated with early-onset severe obesity, hyperphagia, and metabolic abnormalities^[4][5][6]. In experimental and clinical studies, MC4R pathway dysfunction has therefore become a widely used model for investigating genetic obesity and energy-homeostasis disorders^[2][4]. Compared with the closely related melanocortin receptor MC3R, MC4R exhibits a distinct and non-redundant role in body-weight regulation; studies in knockout models indicate that MC3R and MC4R contribute independently and complementarily to energy homeostasis rather than serving interchangeable functions^[7]. For experimental applications, selective MC4R agonists, particularly setmelanotide, have demonstrated the ability to restore signaling in subsets of impaired MC4R variants and induce weight loss in MC4R-deficient obesity, supporting their utility as pharmacological tools and therapeutic candidates for melanocortin-pathway research^[8][9][10].