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dc.contributor.authorPearce, Laura Ren
dc.contributor.authorAtanassova, Nelien
dc.contributor.authorBanton, Matthewen
dc.contributor.authorBottomley, Billen
dc.contributor.authorvan, der Klaauw Agatha Aen
dc.contributor.authorRevelli, Jean-Pierreen
dc.contributor.authorHendricks, Audreyen
dc.contributor.authorKeogh, Juliaen
dc.contributor.authorHenning, Elanaen
dc.contributor.authorDoree, Deonen
dc.contributor.authorJeter-Jones, Sabrinaen
dc.contributor.authorGarg, Sumedhaen
dc.contributor.authorBochukova, Elena Gen
dc.contributor.authorBounds, Rebeccaen
dc.contributor.authorAshford, Sofieen
dc.contributor.authorGayton, Emmaen
dc.contributor.authorHindmarsh, Peter Cen
dc.contributor.authorShield, Julian PHen
dc.contributor.authorCrowne, Elizabethen
dc.contributor.authorBarford, Daviden
dc.contributor.authorWareham, Nicholasen
dc.contributor.authorRaymond, Lucyen
dc.contributor.authorO’Rahilly, Stephenen
dc.contributor.authorMurphy, Mikeen
dc.contributor.authorPowell, David Ren
dc.contributor.authorBarroso, Inesen
dc.contributor.authorFarooqi, Ismaaen
dc.date.accessioned2015-03-17T15:10:45Z
dc.date.available2015-03-17T15:10:45Z
dc.date.issued2013-10-24en
dc.identifier.citationCell Volume 155, Issue 4, p765–777, 7 November 2013. DOI: 10.1016/j.cell.2013.09.058en
dc.identifier.issn0092-8674
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247053
dc.description.abstractKinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.
dc.description.sponsorshipThis work was supported by the Wellcome Trust (098497/Z/12/Z; 077016/Z/05/Z; 096106/Z/11/Z) (ISF and LRP), Medical Research Council (MC_U106179471) (NW), NIHR Cambridge Biomedical Research Centre (ISF, IB and SOR), and European Research Council (ISF). This study makes use of data generated by the UK10K Consortium (WT091310). A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org.
dc.languageEnglishen
dc.language.isoenen
dc.publisherCell Press (Elsevier)
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.titleKSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidationen
dc.typeArticle
dc.description.versionThis is the final published version. It first appeared at http://www.cell.com/abstract/S0092-8674%2813%2901276-2.en
prism.endingPage777
prism.publicationDate2013en
prism.publicationNameCellen
prism.startingPage765
prism.volume155en
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderMRC
dc.rioxxterms.funderNIHR
dc.rioxxterms.funderERC
dc.rioxxterms.projectid098497/Z/12/Z
dc.rioxxterms.projectid077016/Z/05/Z
dc.rioxxterms.projectid096106/Z/11/Z
dc.rioxxterms.projectidMC_U106179471
dcterms.dateAccepted2013-09-20en
rioxxterms.versionofrecord10.1016/j.cell.2013.09.058en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2013-10-24en
dc.contributor.orcidKeogh, Julia [0000-0002-0399-4114]
dc.contributor.orcidHenning, Elana [0000-0002-0399-4114]
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.contributor.orcidRaymond, Lucy [0000-0003-2652-3355]
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.contributor.orcidBarroso, Ines [0000-0001-5800-4520]
dc.contributor.orcidFarooqi, Ismaa [0000-0001-7609-3504]
dc.identifier.eissn1097-4172
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (096106/Z/11/Z)
pubs.funder-project-idWELLCOME TRUST (098497/Z/12/Z)
pubs.funder-project-idMRC (G0502115)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (G0900554)
pubs.funder-project-idMRC (MC_UU_12012/1)
pubs.funder-project-idMRC (MC_UU_12015/1)
pubs.funder-project-idMRC (G0600717B)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5/B)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
pubs.funder-project-idWellcome Trust (099038/Z/12/Z)
pubs.funder-project-idWellcome Trust (100574/Z/12/Z)
pubs.funder-project-idMedical Research Council (MC_U106179471)
pubs.funder-project-idWellcome Trust (091310/Z/10/Z)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales