What are melanocortins?

The melanocortin system consists of a parent hormone — proopiomelanocortin (POMC) — that is cleaved into several peptide fragments (α-MSH, β-MSH, γ-MSH, ACTH, β-endorphin) and a family of five G-protein-coupled receptors (MC1R through MC5R), each expressed on different tissues and driving different physiological effects.

MC1R is on melanocytes and controls pigmentation. Activation shifts biosynthesis from pheomelanin toward eumelanin, giving photoprotection. This is the mechanism behind Melanotan I (afamelanotide / Scenesse, approved for erythropoietic protoporphyria) and Melanotan II. MC2R is on adrenal cortex and mediates ACTH's cortisol-release signal. MC3R and MC4R are central-nervous-system receptors involved in appetite regulation and sexual response. MC4R loss-of-function is the most common single-gene cause of severe childhood obesity. Setmelanotide (Imcivree) is an MC4R agonist approved for specific monogenic obesities. Bremelanotide (PT-141, Vyleesi) engages MC4R for female hypoactive sexual desire disorder. MC5R is on sebaceous and exocrine glands.

An important editorial thread in this system: the anti-inflammatory activity of α-MSH survives in its C-terminal tripeptide fragment KPV, which suppresses NF-κB nuclear translocation. KPV appears in tissue-repair blends because its inflammation control complements structural repair peptides.