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dc.contributor.authorSebaa, Ren_US
dc.contributor.authorJohnson, Jen_US
dc.contributor.authorPileggi, Cen_US
dc.contributor.authorNorgren, Men_US
dc.contributor.authorXuan, Jen_US
dc.contributor.authorSai, Yen_US
dc.contributor.authorTong, Qen_US
dc.contributor.authorKrystkowiak, Ien_US
dc.contributor.authorBondy-Chorney, Een_US
dc.contributor.authorDavey, NEen_US
dc.contributor.authorKrogan, Nen_US
dc.contributor.authorDowney, Men_US
dc.contributor.authorHarper, M-Een_US
dc.coverage.spatialGermanyen_US
dc.date.accessioned2019-05-14T09:34:05Z
dc.date.issued2019-04-17en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/31060926en_US
dc.identifierS2212-8778(18)30958-Xen_US
dc.identifier.citationMol Metab, 2019en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3225
dc.identifier.eissn2212-8778en_US
dc.identifier.doi10.1016/j.molmet.2019.04.008en_US
dc.description.abstractOBJECTIVE: Brown adipose tissue (BAT) is important for thermoregulation in many mammals. Uncoupling protein 1 (UCP1) is the critical regulator of thermogenesis in BAT. Here we aimed to investigate the deacetylation control of BAT and to investigate a possible functional connection between UCP1 and sirtuin 3 (SIRT3), the master mitochondrial lysine deacetylase. METHODS: We carried out physiological, molecular, and proteomic analyses of BAT from wild-type and Sirt3KO mice when BAT is activated. Mice were either cold exposed for 2 days or were injected with the β3-adrenergic agonist, CL316,243 (1 mg/kg; i.p.). Mutagenesis studies were conducted in a cellular model to assess the impact of acetylation lysine sites on UCP1 function. Cardiac punctures were collected for proteomic analysis of blood acylcarnitines. Isolated mitochondria were used for functional analysis of OXPHOS proteins. RESULTS: Our findings showed that SIRT3 absence in mice resulted in impaired BAT lipid use, whole body thermoregulation, and respiration in BAT mitochondria, without affecting UCP1 expression. Acetylome profiling of BAT mitochondria revealed that SIRT3 regulates acetylation status of many BAT mitochondrial proteins including UCP1 and crucial upstream proteins. Mutagenesis work in cells suggested that UCP1 activity was independent of direct SIRT3-regulated lysine acetylation. However, SIRT3 impacted BAT mitochondrial proteins activities of acylcarnitine metabolism and specific electron transport chain complexes, CI and CII. CONCLUSIONS: Our data highlight that SIRT3 likely controls BAT thermogenesis indirectly by targeting pathways upstream of UCP1.en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAcetylationen_US
dc.subjectAcylcarnitinesen_US
dc.subjectBrown adipose tissueen_US
dc.subjectFatty acid oxidationen_US
dc.subjectMitochondriaen_US
dc.subjectOxidative phosphorylationen_US
dc.subjectSirtuin 3en_US
dc.subjectThermogenesisen_US
dc.subjectThermoregulationen_US
dc.subjectUncoupling protein 1en_US
dc.titleSIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-04-11en_US
rioxxterms.versionofrecord10.1016/j.molmet.2019.04.008en_US
rioxxterms.licenseref.startdate2019-04-17en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfMol Metaben_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.publication-statusPublished onlineen_US
pubs.embargo.termsNot knownen_US
dc.contributor.icrauthorDavey, Normanen_US


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