alpha-MSH

In two multicenter, randomized, double-blind, placebo-controlled trials, subcutaneous implants of the alpha-MSH analogue afamelanotide (16 mg) significantly increased pain-free sun-exposure time in patients with erythropoietic protoporphyria (EPP), a disorder of ferrochelatase deficiency causing severe phototoxicity. By activating MC1R-driven eumelanin synthesis, afamelanotide raised cutaneous melanin density and photoprotection, improving quality-of-life scores versus placebo with an acceptable safety profile. The trials provided the pivotal evidence supporting regulatory approval of afamelanotide (Scenesse) as the first therapy for EPP.

People with the rare inherited condition EPP get severe burning pain within minutes of sunlight. This study tested afamelanotide, a lab-made version of the hormone that makes skin tan, given as a small under-the-skin implant. Patients who received it could spend more time in the sun without pain and reported a better quality of life, which led to the drug becoming the first approved treatment for the disease.

Sequencing of the melanocortin-1 receptor (MC1R) gene revealed loss-of-function variants present in over 80% of individuals with red hair and/or fair skin that tans poorly, but in fewer than 20% of those with brown/black hair and good tanning ability. Because MC1R is the receptor through which alpha-MSH signals melanocytes to switch from red/yellow pheomelanin to photoprotective eumelanin, these variants impair the alpha-MSH response and bias pigment production toward pheomelanin. This established MC1R as a key determinant of human pigmentation phenotype and UV sensitivity.

This study found that specific changes in a gene called MC1R are strongly linked to having red hair and pale skin that burns rather than tans. MC1R is the docking site that the tanning hormone alpha-MSH uses to tell skin cells to make dark, protective pigment. When the gene is altered, that signal works poorly, so the skin makes reddish pigment instead and is more vulnerable to the sun.

Gene-targeted inactivation of the melanocortin-4 receptor (MC4R) in mice produced a maturity-onset obesity syndrome characterized by hyperphagia, hyperinsulinemia, hyperglycemia, and increased linear growth, with a clear gene-dosage effect in heterozygotes. Since MC4R is a central target of alpha-MSH (derived from POMC), the results demonstrated that alpha-MSH/MC4R signaling in the hypothalamus tonically suppresses food intake and regulates energy homeostasis. This work defined the central melanocortin pathway as a principal regulator of body weight, later confirmed by human MC4R mutations being the most common cause of monogenic obesity.

Researchers bred mice lacking a brain receptor called MC4R, and these mice ate more and became obese. This receptor normally receives the alpha-MSH hormone signal that tells the brain to stop eating. The experiment showed this hormone pathway is a master switch for appetite and body weight, a finding that later explained a common genetic cause of obesity in people.