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dc.contributor.authorSebaa, R
dc.contributor.authorJohnson, J
dc.contributor.authorPileggi, C
dc.contributor.authorNorgren, M
dc.contributor.authorXuan, J
dc.contributor.authorSai, Y
dc.contributor.authorTong, Q
dc.contributor.authorKrystkowiak, I
dc.contributor.authorBondy-Chorney, E
dc.contributor.authorDavey, NE
dc.contributor.authorKrogan, N
dc.contributor.authorDowney, M
dc.contributor.authorHarper, M-E
dc.date.accessioned2019-05-14T09:34:05Z
dc.date.issued2019-07
dc.identifier.citationMolecular metabolism, 2019, 25 pp. 35 - 49
dc.identifier.issn2212-8778
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3225
dc.identifier.eissn2212-8778
dc.identifier.doi10.1016/j.molmet.2019.04.008
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.
dc.formatPrint-Electronic
dc.format.extent35 - 49
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectMitochondria
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectCarbon-Carbon Double Bond Isomerases
dc.subjectRacemases and Epimerases
dc.subjectEnoyl-CoA Hydratase
dc.subject3-Hydroxyacyl CoA Dehydrogenases
dc.subjectAcetyl-CoA C-Acyltransferase
dc.subjectCarnitine
dc.subjectMitochondrial Proteins
dc.subjectModels, Animal
dc.subjectProteomics
dc.subjectMutagenesis
dc.subjectBody Composition
dc.subjectAcetylation
dc.subjectOxidative Phosphorylation
dc.subjectBody Temperature Regulation
dc.subjectThermogenesis
dc.subjectMale
dc.subjectAdipose Tissue, Brown
dc.subjectSirtuin 3
dc.subjectHEK293 Cells
dc.subjectAdrenergic beta-3 Receptor Antagonists
dc.subjectUncoupling Protein 1
dc.titleSIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1.
dc.typeJournal Article
dcterms.dateAccepted2019-04-11
rioxxterms.versionofrecord10.1016/j.molmet.2019.04.008
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
rioxxterms.licenseref.startdate2019-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular metabolism
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.publication-statusPublished
pubs.volume25
pubs.embargo.termsNot known
dc.contributor.icrauthorDavey, Normanen


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