Melanocortin 3 and 4 receptors (MC3R/MC4R)

The Melanocortin 3 and 4 receptors (MC3R and MC4R) are G protein-coupled receptors primarily expressed in the central nervous system, particularly within the hypothalamus and brainstem. They serve as critical components of the leptin-melanocortin pathway, which is the primary central circuit regulating energy homeostasis, appetite, and body weight (nih.gov, 2024). MC4R is the major mediator of satiety and energy expenditure; its activation by alpha-melanocyte-stimulating hormone (α-MSH) inhibits food intake, while its antagonism by agouti-related protein (AgRP) promotes hunger (nih.gov, 2023). MC3R plays a complementary, non-redundant role in nutrient partitioning, metabolic flexibility, and the regulation of growth, puberty, and circadian rhythms (jcrpe.org, 2021). Mutations in the MC4R gene are recognized as the most common cause of monogenic human obesity, accounting for 1–6% of morbidly obese individuals (nih.gov, 2020). Therapeutic targeting of these receptors has led to the development of agonists like setmelanotide for treating rare genetic obesity disorders and bremelanotide for hypoactive sexual desire disorder (rxlist.com, 2024). However, drug development faces challenges such as off-target hyperpigmentation via MC1R and cardiovascular side effects like increased blood pressure and heart rate due to sympathetic nervous system activation (mdpi.com, 2023).

Other names

MC3-RMC4-RNeural melanocortin receptorsMelanocortin receptor 3Melanocortin receptor 4

Agonism of MC4R and MC3R to induce satiety and increase energy expenditure for obesity treatment; Agonism of MC4R to treat sexual dysfunction; Antagonism of MC4R/MC3R to treat cachexia and wasting syndromes.