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dc.contributor.authorKrycer, James Ren
dc.contributor.authorElkington, Sarah Den
dc.contributor.authorDiaz-Vegas, Alexisen
dc.contributor.authorCooke, Kristen Cen
dc.contributor.authorBurchfield, James Gen
dc.contributor.authorFisher-Wellman, Kelsey Hen
dc.contributor.authorCooney, Gregory Jen
dc.contributor.authorFazakerley, Danielen
dc.contributor.authorJames, David Een
dc.date.accessioned2019-11-27T00:32:18Z
dc.date.available2019-11-27T00:32:18Z
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/299328
dc.description.abstractInsulin action in adipose tissue is crucial for whole-body glucose homeostasis, with insulin resistance being a major risk factor for metabolic diseases such as type 2 diabetes. Recent studies have proposed mitochondrial oxidants as a unifying driver of adipose insulin resistance, serving as a signal of nutrient excess. However, neither the substrates for nor sites of oxidant production are known. Since insulin stimulates glucose utilisation, we hypothesised that glucose oxidation would fuel respiration, in turn generating mitochondrial oxidants. This would impair insulin action, limiting further glucose uptake in a negative feedback loop of ‘glucose-dependent’ insulin resistance. Using primary rat adipocytes and cultured 3T3-L1 adipocytes, we observed that insulin increased respiration, but notably this occurred independently of glucose supply. In contrast, glucose was required for insulin to increase mitochondrial oxidants. Despite rising to similar levels as when treated with other agents that cause insulin resistance, glucose-dependent mitochondrial oxidants failed to cause insulin resistance. Subsequent studies revealed a temporal relationship whereby mitochondrial oxidants needed to increase before the insulin stimulus to induce insulin resistance. Together, these data reveal that a) adipocyte respiration is principally fuelled from non-glucose sources, b) there is a disconnect between respiration and oxidative stress, whereby mitochondrial oxidant levels do not rise with increased respiration unless glucose is present, and c) mitochondrial oxidative stress must precede the insulin stimulus to cause insulin resistance, explaining why short-term insulin-dependent glucose utilisation does not promote insulin resistance. These data provide additional clues to mechanistically link nutrient excess to adipose insulin resistance.
dc.description.sponsorshipDEJ was supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (APP1019680) and NHMRC project grants (GNT1061122, GNT1086851). GJC was supported by a Professorial Research Fellowship from the University of Sydney Medical School. DEJ and GJC were also supported by an NHMRC project grant (GNT1086850). JRK was funded by an NHMRC Early Career Fellowship (APP1072440), Australian Diabetes Society Skip Martin Early-Career Fellowship, Diabetes Australia Research Program grant, and CPC Early-Career Seed Funding grant. DJF was funded by Medical Research Council Career Development Award (MR/S007091/1).
dc.languageenen
dc.publisherAmerican Society for Biochemistry & Molecular Biology (ASBMB)
dc.rightsAll rights reserved
dc.rights.uri
dc.titleMitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytesen
dc.typeArticle
prism.publicationNameJournal of Biological Chemistryen
dc.identifier.doi10.17863/CAM.46396
dcterms.dateAccepted2019-11-19en
rioxxterms.versionofrecord10.1074/jbc.ra119.011695en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-11-19en
dc.contributor.orcidFazakerley, Daniel [0000-0001-8241-2903]
dc.identifier.eissn1083-351X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/S007091/1)
cam.issuedOnline2019-11-19en
cam.orpheus.successThu Jan 30 10:35:05 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2019-11-19


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