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dc.contributor.authorKirwan, Peteren
dc.contributor.authorKay, Richarden
dc.contributor.authorBrouwers, Basen
dc.contributor.authorHerranz-Pérez, Vicenteen
dc.contributor.authorJura, Magdalenaen
dc.contributor.authorLarraufie, Pierreen
dc.contributor.authorJerber, Julieen
dc.contributor.authorPembroke, Jasonen
dc.contributor.authorBartels, Theresaen
dc.contributor.authorWhite, Anneen
dc.contributor.authorGribble, Fionaen
dc.contributor.authorReimann, Franken
dc.contributor.authorFarooqi, Ismaaen
dc.contributor.authorO'Rahilly, Stephenen
dc.contributor.authorMerkle, Florianen
dc.date.accessioned2018-11-14T00:31:41Z
dc.date.available2018-11-14T00:31:41Z
dc.date.issued2018-11en
dc.identifier.issn2212-8778
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285059
dc.description.abstractObjective: The lack of pro-opiomelanocortin (POMC)-derived melanocortin peptides results in hypoadrenalism and severe obesity in both humans and rodents that is treatable with synthetic melanocortins. However, there are significant differences in POMC processing between humans and rodents, and little is known about the relative physiological importance of POMC products in the human brain. The aim of this study was to determine which POMC peptides are present in the human brain, to establish their relative concentrations, and to test if their production is dynamically regulated. Methods: We analysed both fresh post-mortem human hypothalamic tissue and hypothalamic neurons derived from human pluripotent stem cells (hPSCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine the sequence and quantify production of hypothalamic neuropeptides, including those derived from POMC. Results: In both in vitro and in vivo hypothalamic cells, LC-MS/MS revealed the sequence of hundreds of neuropeptides as a resource for the field. Although the existence of beta-melanocyte stimulating hormone (MSH) is controversial, we found that both this peptide and desacetyl alpha-MSH (d-alpha-MSH) were produced in considerable excess of acetylated alpha-MSH. In hPSC-derived hypothalamic neurons, these POMC derivatives were appropriately trafficked, secreted, and their production was significantly (P<0.0001) increased in response to the hormone leptin. Conclusions: Our findings challenge the assumed pre-eminence of beta-MSH and suggest that in humans, d-alpha-MSH and beta-MSH are likely to be the predominant physiological products acting on melanocortin receptors.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHypothalamusen
dc.subjectNeuronsen
dc.subjectPluripotent Stem Cellsen
dc.subjectHumansen
dc.subjectLeptinen
dc.subjectPro-Opiomelanocortinen
dc.subjectalpha-MSHen
dc.subjectbeta-MSHen
dc.subjectNeuropeptidesen
dc.subjectReceptors, Melanocortinen
dc.subjectChromatography, Liquiden
dc.subjectHomeostasisen
dc.subjectFemaleen
dc.subjectMaleen
dc.subjectMass Spectrometryen
dc.subjectTandem Mass Spectrometryen
dc.subjectMelanocortinsen
dc.titleQuantitative mass spectrometry for human melanocortin peptides in vitro and in vivo suggests prominent roles for β-MSH and desacetyl α-MSH in energy homeostasis.en
dc.typeArticle
prism.endingPage97
prism.publicationDate2018en
prism.publicationNameMolecular metabolismen
prism.startingPage82
prism.volume17en
dc.identifier.doi10.17863/CAM.32429
dcterms.dateAccepted2018-08-16en
rioxxterms.versionofrecord10.1016/j.molmet.2018.08.006en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-11en
dc.contributor.orcidKirwan, Peter [0000-0003-1446-7544]
dc.contributor.orcidKay, Richard [0000-0002-3827-8687]
dc.contributor.orcidBrouwers, Bas [0000-0001-6541-4835]
dc.contributor.orcidHerranz-Pérez, Vicente [0000-0002-1969-1214]
dc.contributor.orcidLarraufie, Pierre [0000-0001-7718-6200]
dc.contributor.orcidPembroke, Jason [0000-0002-4265-135X]
dc.contributor.orcidWhite, Anne [0000-0002-7686-2884]
dc.contributor.orcidGribble, Fiona [0000-0002-4232-2898]
dc.contributor.orcidReimann, Frank [0000-0001-9399-6377]
dc.contributor.orcidFarooqi, Ismaa [0000-0001-7609-3504]
dc.contributor.orcidO'Rahilly, Stephen [0000-0003-2199-4449]
dc.contributor.orcidMerkle, Florian [0000-0002-8513-2998]
dc.identifier.eissn2212-8778
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (100574/Z/12/Z)
pubs.funder-project-idMRC (MC_UU_12012/1)
pubs.funder-project-idMRC (MC_UU_12012/5)
pubs.funder-project-idWELLCOME TRUST (105602/Z/14/Z)
pubs.funder-project-idAcademy of Medical Sciences (Springboard)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (MR/M009041/1)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (G0900554)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idMRC (MC_UU_12012/3)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (MR/M024873/1)
pubs.funder-project-idMRC (MC_UU_00014/3)
pubs.funder-project-idMRC (MC_UU_00014/5)
pubs.funder-project-idMRC (MR/P501967/1)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International