Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
dc.contributor.author | Yang, Y | |
dc.contributor.author | van der Klaauw, AA | |
dc.contributor.author | Zhu, L | |
dc.contributor.author | Cacciottolo, TM | |
dc.contributor.author | He, Y | |
dc.contributor.author | Stadler, LKJ | |
dc.contributor.author | Wang, C | |
dc.contributor.author | Xu, P | |
dc.contributor.author | Saito, K | |
dc.contributor.author | Hinton, A | |
dc.contributor.author | Yan, X | |
dc.contributor.author | Keogh, JM | |
dc.contributor.author | Henning, E | |
dc.contributor.author | Banton, Matthew | |
dc.contributor.author | Hendricks, AE | |
dc.contributor.author | Bochukova, EG | |
dc.contributor.author | Mistry, V | |
dc.contributor.author | Lawler, KL | |
dc.contributor.author | Liao, L | |
dc.contributor.author | Xu, J | |
dc.contributor.author | O’Rahilly, S | |
dc.contributor.author | Tong, Q | |
dc.contributor.author | Inês Barroso, | |
dc.contributor.author | O’Malley, BW | |
dc.contributor.author | Farooqi, IS | |
dc.contributor.author | Xu, Y | |
dc.date.accessioned | 2020-07-16T10:31:30Z | |
dc.date.available | 2020-07-16T10:31:30Z | |
dc.date.issued | 2019-12 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.other | 1718 | |
dc.identifier.uri | http://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.extent | 1718- | |
dc.format.medium | Electronic | |
dc.language | en | |
dc.language.iso | en | |
dc.publisher | Springer Science and Business Media LLC | |
dc.subject | Alleles | |
dc.subject | Animals | |
dc.subject | Body Weight | |
dc.subject | Cell Line, Tumor | |
dc.subject | Crosses, Genetic | |
dc.subject | Gene Deletion | |
dc.subject | Gene Knock-In Techniques | |
dc.subject | Genetic Variation | |
dc.subject | HEK293 Cells | |
dc.subject | Heterozygote | |
dc.subject | Homeostasis | |
dc.subject | Humans | |
dc.subject | Hypothalamus | |
dc.subject | Leptin | |
dc.subject | Male | |
dc.subject | Membrane Potentials | |
dc.subject | Mice | |
dc.subject | Mice, Transgenic | |
dc.subject | Mutation, Missense | |
dc.subject | Neurons | |
dc.subject | Nuclear Receptor Coactivator 1 | |
dc.subject | Obesity | |
dc.subject | Phenotype | |
dc.title | Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis | |
dc.type | journal-article | |
dc.type | Journal Article | |
dc.type | Research Support, N.I.H., Extramural | |
dc.type | Research Support, Non-U.S. Gov't | |
dc.type | Research Support, U.S. Gov't, Non-P.H.S. | |
plymouth.author-url | https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000464338100029&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008 | |
plymouth.issue | 1 | |
plymouth.volume | 10 | |
plymouth.publication-status | Published online | |
plymouth.journal | Nature Communications | |
dc.identifier.doi | 10.1038/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.place | England | |
dcterms.dateAccepted | 2019-01-21 | |
dc.rights.embargodate | 2020-7-29 | |
dc.identifier.eissn | 2041-1723 | |
dc.rights.embargoperiod | Not known | |
rioxxterms.versionofrecord | 10.1038/s41467-019-08737-6 | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2019-12 | |
rioxxterms.type | Journal Article/Review |