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Evolved from light\u2010responsive pigment mechanisms, these peptides were repurposed into hypothalamic circuits regulating energy balance, circadian rhythms, and complex behaviors. Their antagonism manifests across multiple biological scales. In the skin, MCH induces melanosome aggregation in low light, whereas MSH promotes their dispersion for ultraviolet protection. In the brain, this pigmentary logic was repurposed into circadian and metabolic regulation: MCH promotes feeding, energy conservation, and sleep, while MSH drives satiety, thermogenesis, and wakefulness. Strikingly, their antagonism extends to subcellular organelles. MCH shortens neuronal primary cilia, whereas MSH elongates them, paralleling their opposite actions on melanosomes. Both processes depend on cAMP\u2013PKA\u2013regulated microtubule transport, reflecting a conserved cellular architecture probably rooted in the shared neural crest origins of melanocytes and neurons. Importantly, these pathways remain tightly entrained to the circadian clock, translating external light\u2212dark cycles into rhythmic control of skin pigmentation and the body's internal metabolic state. Disruptions of these systems contribute to diverse metabolic and neuropsychiatric disorders, often through opposite imbalances of signaling, and understanding this deep evolutionary continuity reveals new therapeutic targets, from receptor ligands to circadian interventions and cilia\u2010targeted therapies.<\/jats:p>","DOI":"10.1111\/nyas.70267","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T17:43:46Z","timestamp":1777139026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Skin to Brain: Antagonism and Parallelism in the MCH and MSH Systems"],"prefix":"10.1111","volume":"1558","author":[{"given":"Amal","family":"Alachkar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences University of California, Irvine  Irvine California USA"},{"name":"UC Irvine Artificial Intelligence in Science Institute University of California, Irvine  Irvine California USA"},{"name":"UC Irvine Center For the Neurobiology of Learning and Memory University of California, Irvine  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Civelli","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences University of California, Irvine  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0196\u20109781(93)90128\u20104"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2012.10.001"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2017.04.008"},{"key":"e_1_2_12_5_1","first-page":"175","volume-title":"The Melanocortins: Genesis, Function, and Therapeutic Potential","author":"Sherbrooke W. 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