MC3R vs MC4R

MC3R and MC4R are the two melanocortin receptors expressed mainly in the brain. Both are Gs-coupled GPCRs stimulated by alpha-MSH cleaved from proopiomelanocortin and opposed by agouti-related peptide, which behaves as an inverse agonist rather than a simple blocker. MC4R sits postsynaptically on paraventricular and brainstem neurons that read the arcuate signal; MC3R sits largely presynaptically on arcuate neurons themselves, including the AgRP cells.

Loss-of-function MC4R variants are the commonest monogenic cause of human obesity, carried by roughly one percent of people with severe early-onset obesity, and heterozygotes are hyperphagic from infancy. MC3R variants produce no such phenotype; they associate instead with lower lean mass and later puberty. Setmelanotide, an MC4R agonist, was approved by the FDA in 2020 for obesity due to POMC, PCSK1 or LEPR deficiency and extended to Bardet-Biedl syndrome in 2022.

That asymmetry is why melanocortin drug programmes target MC4R and largely ignore MC3R. It is also why an MC4R agonist is not a general obesity drug: where the receptor itself is broken, agonism has nothing to act on, so setmelanotide's label is written around specific genetic diagnoses rather than a BMI cut-off. Raised blood pressure and darkened skin are on-target MC4R effects, not impurities.

The recurring error is treating any melanocortin agonist as an MC4R drug. Melanotan II, sold unapproved, is non-selective and hits MC1R hardest, which is where the tanning comes from; its appetite and erectile effects come from central receptors it also touches, at exposures never characterised in a controlled human trial. Bremelanotide, its approved relative, was licensed in 2019 for hypoactive sexual desire, not for weight.