# Melanocyte-stimulating hormone
**Melanocyte-stimulating hormone** (MSH) is a group of peptide hormones, called melanotropins, that stimulate pigmented cells to synthesize and distribute melanin, thereby increasing the coloration of skin and other tissue. In mammals the group comprises α-MSH, β-MSH, and γ-MSH, all cleaved from the precursor protein proopiomelanocortin (POMC); together with adrenocorticotropic hormone (ACTH) they form the melanocortin family.[1](https://www.ncbi.nlm.nih.gov/mesh/68009074) • [2](https://www.sciencedirect.com/science/article/pii/B9780128206492000589)
| Key fact | Detail |
|---|---|
| Peptides | α-MSH, β-MSH, and γ-MSH, generated from POMC by posttranslational proteolytic cleavage[2](https://www.sciencedirect.com/science/article/pii/B9780128206492000589) |
| Structure | α-MSH is Ac-ACTH(1–13)-NH2, a 13-amino-acid sequence embedded within the 39-amino-acid ACTH[3](https://doi.org/10.1530/JME-15-0292) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4899099/) |
| Core motif | All melanocortin peptides share the conserved tetrapeptide His-Phe-Arg-Trp, essential for binding melanocortin receptors[5](https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.651236/full) |
| Main sources | Melanotrophs of the pituitary intermediate lobe, corticotrophs of the anterior lobe, and arcuate nucleus neurons of the hypothalamus[1](https://www.ncbi.nlm.nih.gov/mesh/68009074) |
| Receptors | Bind MC1R, MC3R, MC4R, and MC5R, but not the ACTH-specific MC2R[2](https://www.sciencedirect.com/science/article/pii/B9780128206492000589) |
| Representative function | Pigmentation of skin and hair via MC1R on melanocytes[6](https://journals.physiology.org/doi/full/10.1152/ajpendo.00434.2002) |
| Human caveat | The adult human pituitary has no pars intermedia, so adult POMC processing to MSH peptides is limited[2](https://www.sciencedirect.com/science/article/pii/B9780128206492000589) |
## Origin and structure
The melanocortin peptides are cut from a single precursor, POMC, a 266-amino-acid protein, by prohormone convertases, carboxypeptidases, and peptidylglycine α-amidating monooxygenase.[7](https://www.ncbi.nlm.nih.gov/books/NBK279116/) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4899099/) In the pituitary intermediate lobe and hypothalamus, more extensive processing than in the anterior lobe yields α-MSH and β-endorphin. α-MSH is formed by acetylation and amidation of the first thirteen residues of ACTH, giving Ac-ACTH(1–13)-NH2; the intermediate product before acetylation is called des-acetyl α-MSH.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4899099/) • [8](https://journals.physiology.org/doi/10.1152/physrev.00024.2017) γ-MSH comes from the amino-terminal region of POMC: the human sequence allows cleavage of N-POMC into a 27-amino-acid γ3-MSH, which can be trimmed to the dodecapeptide γ2-MSH and then to the 11-amino-acid γ1-MSH, though glycosylation at Asn16 can restrict this processing.[8](https://journals.physiology.org/doi/10.1152/physrev.00024.2017)
Species differences matter. Rats and mice lack the dibasic residues needed to cleave out β-MSH, so no β-MSH is produced from rodent POMC, and rodents appear to have only the extended γ3-MSH peptide.[8](https://journals.physiology.org/doi/10.1152/physrev.00024.2017) • [9](https://www.endocrine.org/journals/endocrinology/obesity-pomc-and-pomc-processing-enzymes) A source note on POMC processing adds that β-MSH in humans may not occur naturally.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4899099/)
## Production and regulation
MSH peptides are produced by melanotrophs in the pituitary intermediate lobe, by corticotrophs in the anterior lobe, and by hypothalamic neurons of the arcuate nucleus.[1](https://www.ncbi.nlm.nih.gov/mesh/68009074) Their release from the intermediate lobe is under tonic inhibitory control from the hypothalamus, in which dopamine is a primary regulator.[2](https://www.sciencedirect.com/science/article/pii/B9780128206492000589) In skin, POMC is also processed locally: α-MSH is expressed in human melanocytes and keratinocytes, and its production is stimulated by corticotropin-releasing factor signaling after prolonged sun exposure.[10](https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2016.00095/full) • [11](https://rmj.com.ro/articles/2019.4/RMJ_2019_4_Art-02.pdf)
## Receptors
The melanocortin peptides act through five melanocortin receptors, MC1R through MC5R, named in the order they were discovered rather than by localization or ligand.[8](https://journals.physiology.org/doi/10.1152/physrev.00024.2017) MSH peptides bind MC1R, MC3R, MC4R, and MC5R, but not MC2R, which is activated only by ACTH and has no affinity for α-, β-, or γ-MSH.[2](https://www.sciencedirect.com/science/article/pii/B9780128206492000589) • [6](https://journals.physiology.org/doi/full/10.1152/ajpendo.00434.2002) MC2R also requires the accessory protein MRAP to reach the cell surface and function.[8](https://journals.physiology.org/doi/10.1152/physrev.00024.2017) The endogenous antagonists are Agouti and agouti-related protein (AGRP), the only known naturally occurring antagonists for these receptors.[12](https://www.sciencedirect.com/science/article/pii/S0925443917301370)
Ligand selectivity differs by receptor. At human MC1R and MC5R, α-MSH has the highest affinity of the four major endogenous melanocortins; MC3R prefers γ1-MSH, and MC4R prefers β-MSH.[13](https://www.mdpi.com/2218-273X/12/10/1407/pdf?version=1664622999) In cultured human melanocytes, the order of affinity and potency for stimulating cAMP formation, tyrosinase activity, and proliferation was α-MSH = ACTH > β-MSH > γ-MSH, and γ-MSH stimulated cAMP only transiently without affecting proliferation or melanogenesis.[14](https://academic.oup.com/endo/article-abstract/137/5/1627/3037675)
## Pigmentation
MC1R is the classical melanocyte α-MSH receptor and has a key role in determining skin and hair pigmentation.[6](https://journals.physiology.org/doi/full/10.1152/ajpendo.00434.2002) Binding of α-MSH or ACTH to MC1R increases both the proliferation and the melanogenesis of cultured human melanocytes, effects mediated specifically through MC1R activation.[14](https://academic.oup.com/endo/article-abstract/137/5/1627/3037675) Variants of MC1R are associated with red hair and pale skin.[15](https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2016.00101/full) In fish and amphibians, α-MSH additionally stimulates pigment dispersion within melanophores for physiological body color change.[2](https://www.sciencedirect.com/science/article/pii/B9780128206492000589)
Clinically, hyperpigmentation in patients with adrenocortical insufficiency or certain pituitary tumors results from increased pituitary release of α-MSH, β-MSH, and ACTH; acquired hyperpigmentation accompanies abnormally high ACTH with high MSH, as in ACTH-secreting tumors of pituitary or non-pituitary origin.[16](https://www.nejm.org/doi/full/10.1056/NEJM196403122701101) • [11](https://rmj.com.ro/articles/2019.4/RMJ_2019_4_Art-02.pdf)
## Other functions
Because melanocortin receptors occur in many tissues, MSH peptides have functions beyond pigmentation. In the central nervous system, α-MSH is the predominant melanocortin peptide regulating feeding and energy homeostasis, acting mainly through MC4R in the melanocortin pathway that controls body weight.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC5027135/) MC1R is also expressed by leukocytes, where it mediates the anti-inflammatory and immunomodulatory properties of melanocortins, and by keratinocytes, fibroblasts, and endothelial cells in skin.[6](https://journals.physiology.org/doi/full/10.1152/ajpendo.00434.2002) MC5R, whose ligand preference places α-MSH first, is associated with sebaceous gland secretion.[6](https://journals.physiology.org/doi/full/10.1152/ajpendo.00434.2002)
## History and clinical ligands
α-MSH, first termed simply MSH before the discovery of β- and γ-MSH, was identified in the porcine pituitary by [Aaron B. Lerner](https://www.edgepedia.org/aaron-b-lerner) and T. B. Lee in 1955; ACTH had been identified in 1930.[10](https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2016.00095/full) Sequencing showed the 13-amino-acid α-MSH embedded within the 39-amino-acid ACTH, a puzzle resolved by the characterization of POMC as their common precursor.[3](https://doi.org/10.1530/JME-15-0292)
The melanocortin system now supplies approved drugs: among clinically approved ligands for melanocortin receptors are ACTH itself, setmelanotide, and bremelanotide, alongside classical ligands such as MSH and agouti-related peptide.[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC9599618/)
## References
1. [Melanocyte-Stimulating Hormones, MeSH, NCBI](https://www.ncbi.nlm.nih.gov/mesh/68009074)
2. [Melanocyte-stimulating hormone, Handbook of Hormones (Second Edition), ScienceDirect](https://www.sciencedirect.com/science/article/pii/B9780128206492000589)
3. [60 YEARS OF POMC: Melanocortin receptors: evolution of ligand selectivity for melanocortin peptides, Journal of Molecular Endocrinology](https://doi.org/10.1530/JME-15-0292)
4. [Biosynthesis, Trafficking and Secretion of Pro-opiomelanocortin-derived peptides, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4899099/)
5. [Melanocortin System in Kidney Homeostasis and Disease, Frontiers in Physiology](https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.651236/full)
6. [The melanocortin system, American Journal of Physiology-Endocrinology and Metabolism](https://journals.physiology.org/doi/full/10.1152/ajpendo.00434.2002)
7. [Normal Physiology of ACTH and GH Release, Endotext, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK279116/)
8. [POMC: The Physiological Power of Hormone Processing, Physiological Reviews](https://journals.physiology.org/doi/10.1152/physrev.00024.2017)
9. [Obesity, POMC, and POMC-Processing Enzymes, Endocrinology](https://www.endocrine.org/journals/endocrinology/obesity-pomc-and-pomc-processing-enzymes)
10. [Melanocortin 1 Receptor: Structure, Function, and Regulation, Frontiers in Genetics](https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2016.00095/full)
11. [High ACTH and skin hyperpigmentation overview, Romanian Medical Journal](https://rmj.com.ro/articles/2019.4/RMJ_2019_4_Art-02.pdf)
12. [Molecular signatures of human melanocortin receptors for ligand binding and signaling, ScienceDirect](https://www.sciencedirect.com/science/article/pii/S0925443917301370)
13. [Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin, Biomolecules](https://www.mdpi.com/2218-273X/12/10/1407/pdf?version=1664622999)
14. [Abdel-Malek et al. (1996). Binding of melanotropic hormones to MC1R on human melanocytes, Endocrinology](https://academic.oup.com/endo/article-abstract/137/5/1627/3037675)
15. [ACTH Antagonists, Frontiers in Endocrinology](https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2016.00101/full)
16. [Melanocyte-Stimulating Hormone and Adrenocorticotrophic Hormone: Their Relation to Pigmentation, New England Journal of Medicine](https://www.nejm.org/doi/full/10.1056/NEJM196403122701101)
17. [60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5027135/)
18. [Ligands for Melanocortin Receptors, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9599618/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Metabolites, cofactors, and biomolecules › Metabolite records › Human metabolites › Specialized human metabolites*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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