Melanocortins
One peptide family, five receptors, strikingly different physiology.
α-MSH · MC1R–MC5R · setmelanotide
Overview
The melanocortin system is built from peptides cleaved from pro-opiomelanocortin (POMC) — α-, β-, and γ-MSH and ACTH — acting on five G-protein-coupled receptors, MC1R through MC5R, each with its own tissue distribution and physiology.
The same ligand family touches pigmentation (MC1R on melanocytes), adrenal steroidogenesis (MC2R/ACTH), energy balance and appetite (MC4R in the hypothalamus), and exocrine and immune functions (MC5R). This receptor-level divergence is what makes the family so biologically broad.
MC4R agonism is the basis of approved therapy for specific genetic obesity, while MC1R pharmacology underlies pigmentation research — the receptors are related but the clinical stories are separate.
Key signals
Core melanocortin ligand; pigmentation, appetite, and anti-inflammatory signaling.
Melanocyte receptor; governs eumelanin vs pheomelanin synthesis.
Hypothalamic receptor; central regulator of appetite and energy balance.
Acts at MC2R to drive adrenal cortisol synthesis — the endocrine arm of the family.
MC4R agonist studied in specific genetic obesity syndromes.
Reference notes
- POMC is a single precursor cleaved tissue-specifically into multiple active peptides — context determines the product.
- Receptor selectivity is the whole game: an MC4R-driven appetite effect and an MC1R-driven pigment effect come from overlapping ligands on different receptors.
- MC4R loss-of-function is one of the most common monogenic causes of obesity, which is why targeted agonism is therapeutically interesting.
- Agonist selectivity across MC1R–MC5R is the key safety and specificity question for any candidate.