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dc.contributor.authorYang, Y
dc.contributor.authorvan der Klaauw, AA
dc.contributor.authorZhu, L
dc.contributor.authorCacciottolo, TM
dc.contributor.authorHe, Y
dc.contributor.authorStadler, LKJ
dc.contributor.authorWang, C
dc.contributor.authorXu, P
dc.contributor.authorSaito, K
dc.contributor.authorHinton, A
dc.contributor.authorYan, X
dc.contributor.authorKeogh, JM
dc.contributor.authorHenning, E
dc.contributor.authorBanton, Matthew
dc.contributor.authorHendricks, AE
dc.contributor.authorBochukova, EG
dc.contributor.authorMistry, V
dc.contributor.authorLawler, KL
dc.contributor.authorLiao, L
dc.contributor.authorXu, J
dc.contributor.authorO’Rahilly, S
dc.contributor.authorTong, Q
dc.contributor.authorInês Barroso,
dc.contributor.authorO’Malley, BW
dc.contributor.authorFarooqi, IS
dc.contributor.authorXu, Y
dc.date.accessioned2020-07-16T10:31:30Z
dc.date.available2020-07-16T10:31:30Z
dc.date.issued2019-12
dc.identifier.issn2041-1723
dc.identifier.issn2041-1723
dc.identifier.other1718
dc.identifier.urihttp://hdl.handle.net/10026.1/16051
dc.description.abstract

<jats:title>Abstract</jats:title><jats:p>Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of <jats:italic>SRC-1</jats:italic> in Pomc neurons in mice attenuates their depolarization by leptin, decreases <jats:italic>Pomc</jats:italic> expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in <jats:italic>SRC-1</jats:italic> found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1<jats:sup>L1376P</jats:sup>), leptin-induced depolarization of Pomc neurons and <jats:italic>Pomc</jats:italic> expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.</jats:p>

dc.format.extent1718-
dc.format.mediumElectronic
dc.languageen
dc.language.isoen
dc.publisherSpringer Science and Business Media LLC
dc.subjectAlleles
dc.subjectAnimals
dc.subjectBody Weight
dc.subjectCell Line, Tumor
dc.subjectCrosses, Genetic
dc.subjectGene Deletion
dc.subjectGene Knock-In Techniques
dc.subjectGenetic Variation
dc.subjectHEK293 Cells
dc.subjectHeterozygote
dc.subjectHomeostasis
dc.subjectHumans
dc.subjectHypothalamus
dc.subjectLeptin
dc.subjectMale
dc.subjectMembrane Potentials
dc.subjectMice
dc.subjectMice, Transgenic
dc.subjectMutation, Missense
dc.subjectNeurons
dc.subjectNuclear Receptor Coactivator 1
dc.subjectObesity
dc.subjectPhenotype
dc.titleSteroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
dc.typejournal-article
dc.typeJournal Article
dc.typeResearch Support, N.I.H., Extramural
dc.typeResearch Support, Non-U.S. Gov't
dc.typeResearch Support, U.S. Gov't, Non-P.H.S.
plymouth.author-urlhttps://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000464338100029&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008
plymouth.issue1
plymouth.volume10
plymouth.publication-statusPublished online
plymouth.journalNature Communications
dc.identifier.doi10.1038/s41467-019-08737-6
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/School of Biomedical Sciences
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.publisher.placeEngland
dcterms.dateAccepted2019-01-21
dc.rights.embargodate2020-7-29
dc.identifier.eissn2041-1723
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1038/s41467-019-08737-6
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-12
rioxxterms.typeJournal Article/Review


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