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Accumulation of succinate controls activation of adipose tissue thermogenesis.

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cam.issuedOnline2018-07-18
dc.contributor.authorMills, Evanna L
dc.contributor.authorPierce, Kerry A
dc.contributor.authorJedrychowski, Mark P
dc.contributor.authorGarrity, Ryan
dc.contributor.authorWinther, Sally
dc.contributor.authorVidoni, Sara
dc.contributor.authorYoneshiro, Takeshi
dc.contributor.authorSpinelli, Jessica B
dc.contributor.authorLu, Gina Z
dc.contributor.authorKazak, Lawrence
dc.contributor.authorBanks, Alexander S
dc.contributor.authorHaigis, Marcia C
dc.contributor.authorKajimura, Shingo
dc.contributor.authorMurphy, Michael P
dc.contributor.authorGygi, Steven P
dc.contributor.authorClish, Clary B
dc.contributor.authorChouchani, Edward T
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.date.accessioned2018-10-10T05:19:52Z
dc.date.available2018-10-10T05:19:52Z
dc.date.issued2018-08
dc.description.abstractThermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease1. Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP-protein kinase A signalling; this pathway has been subject to longstanding clinical investigation2-4. Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signalling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. We identify a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase supresses thermogenesis. Finally, we show that pharmacological elevation of circulating succinate drives UCP1-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically-derived thermogenic molecule.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.30830
dc.identifier.eissn1476-4687
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283464
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41586-018-0353-2
dc.subjectAdipocytes
dc.subjectAdipose Tissue, Brown
dc.subjectAdipose Tissue, White
dc.subjectAnimals
dc.subjectFemale
dc.subjectMale
dc.subjectMetabolomics
dc.subjectMice
dc.subjectObesity
dc.subjectOxidation-Reduction
dc.subjectReactive Oxygen Species
dc.subjectSuccinate Dehydrogenase
dc.subjectSuccinic Acid
dc.subjectThermogenesis
dc.subjectUncoupling Protein 1
dc.titleAccumulation of succinate controls activation of adipose tissue thermogenesis.
dc.typeArticle
dcterms.dateAccepted2018-06-12
prism.endingPage106
prism.issueIdentifier7716
prism.publicationDate2018
prism.publicationNameNature
prism.startingPage102
prism.volume560
pubs.funder-project-idMedical Research Council (MC_UU_00015/3)
pubs.funder-project-idWellcome Trust (110159/Z/15/Z)
rioxxterms.licenseref.startdate2018-08
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1038/s41586-018-0353-2

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