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dc.contributor.authorGroeneveld, Matthijsen
dc.contributor.authorBrierley, Gemmaen
dc.contributor.authorRocha, Nunoen
dc.contributor.authorSiddle, Kennethen
dc.contributor.authorSemple, Roberten
dc.date.accessioned2016-01-18T17:52:40Z
dc.date.available2016-01-18T17:52:40Z
dc.date.issued2016-02-18en
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/253336
dc.description.abstractLoss of function of the insulin receptor (INSR) in humans produces severe insulin resistance. Unlike “common” insulin resistance, this is associated with elevated plasma levels of the insulin-sensitising, adipose-derived protein adiponectin. The underlying mechanism for this paradox is unclear, and it is at odds with the acute stimulation of adiponectin secretion reported on insulin treatment of cultured adipocytes. Given recent evidence for ligand-independent actions of the INSR, we used a lentiviral system to knock down Insr or its substrates Irs1 and Irs2 conditionally in 3T3-L1 murine preadipocytes/adipocytes to assess whether acute loss of their expression has different consequences to withdrawal of insulin. Efficient knockdown of either Insr or Irs1/2 was achieved by conditional shRNA expression, severely attenuating insulin-stimulated AKT phosphorylation and glucose uptake. Dual knockdown of Irs1 and Irs2 but not Insr in preadipocytes impaired differentiation to adipocytes. Acute knockdown of Insr or both Irs1 and Irs2 in adipocytes increased Adipoq mRNA expression but reduced adiponectin secretion, assessed by immunoassay. Knockdown sustained for 14 days also reduced immunoassay-detected adiponectin secretion, and moreover induced delipidation of the cells. These findings argue against a distinct effect of Insr deficiency to promote adiponectin secretion as the explanation for paradoxical insulin receptoropathy-related hyperadiponectinaemia.
dc.description.sponsorshipAdiponectin DELFIA assays were undertaken by the United Kingdom National Institute for Health Research (NIHR) Clinical Biochemistry Assay Laboratory. This work was supported by the Wellcome Trust (grant number WT098498), the Medical Research Council (MRC-MC-UU- 12012/5), and the NIHR Cambridge Biomedical Research Centre.
dc.languageEnglishen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleAcute knockdown of the insulin receptor or its substrates Irs1 and 2 in 3T3-L1 adipocytes suppresses adiponectin productionen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Nature Publishing Group via https://doi.org/10.1038/srep21105en
prism.number21105en
prism.publicationDate2016en
prism.publicationNameScientific Reportsen
prism.volume6en
dc.rioxxterms.funderNIHR
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderMRC
dc.rioxxterms.projectidWT098498
dc.rioxxterms.projectid(MRC-MC-UU-12012/5
dcterms.dateAccepted2016-01-12en
rioxxterms.versionofrecord10.1038/srep21105en
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2016-02-18en
dc.contributor.orcidBrierley, Gemma [0000-0002-4600-9970]
dc.contributor.orcidSemple, Robert [0000-0001-6539-3069]
dc.identifier.eissn2045-2322
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (098498/Z/12/Z)
cam.orpheus.successThu Jan 30 12:55:23 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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