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dc.contributor.authorYe, Lan
dc.contributor.authorVaramini, Behzad
dc.contributor.authorBaur, Joseph A.
dc.contributor.authorSabatini, David
dc.contributor.authorLamming, Dudley W.
dc.date.accessioned2018-07-03T19:13:33Z
dc.date.available2018-07-03T19:13:33Z
dc.date.issued2012-09
dc.identifier.issn1664-8021
dc.identifier.urihttp://hdl.handle.net/1721.1/116773
dc.description.abstractRapamycin, an inhibitor of mTOR complex 1 (mTORC1), improves insulin sensitivity in acute studies in vitro and in vivo by disrupting a negative feedback loop mediated by S6 kinase. We find that rapamycin has a clear biphasic effect on insulin sensitivity in C2C12 myotubes, with enhanced responsiveness during the first hour that declines to almost complete insulin resistance by 24-48 h. We and others have recently observed that chronic rapamycin treatment induces insulin resistance in rodents, at least in part due to disruption of mTORC2, an mTOR-containing complex that is not acutely sensitive to the drug. Chronic rapamycin treatment may also impair insulin action via the inhibition of mTORC1-dependent mitochondrial biogenesis and activity, which could result in a buildup of lipid intermediates that are known to trigger insulin resistance. We confirmed that rapamycin inhibits expression of PGC-1α, a key mitochondrial transcription factor, and acutely reduces respiration rate in myotubes. However, rapamycin did not stimulate phosphorylation of PKCΘ, a central mediator of lipid-induced insulin resistance. Instead, we found dramatic disruption of mTORC2, which coincided with the onset of insulin resistance. Selective inhibition of mTORC1 or mTORC2 by shRNA-mediated knockdown of specific components (Raptor and Rictor, respectively) confirmed that mitochondrial effects of rapamycin are mTORC1-dependent, whereas insulin resistance was recapitulated only by knockdown of mTORC2.Thus, mTORC2 disruption, rather than inhibition of mitochondria, causes insulin resistance in rapamycin-treated myotubes, and this system may serve as a useful model to understand the effects of rapamycin on mTOR signaling in vivo.en_US
dc.publisherFrontiers Research Foundationen_US
dc.relation.isversionofhttp://dx.doi.org/10.3389/fgene.2012.00177en_US
dc.rightsCreative Commons Attribution 4.0 International Licenseen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceFrontiersen_US
dc.titleRapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2en_US
dc.typeArticleen_US
dc.identifier.citationYe, Lan et al. “Rapamycin Has a Biphasic Effect on Insulin Sensitivity in C2C12 Myotubes Due to Sequential Disruption of mTORC1 and mTORC2.” Frontiers in Genetics 3 (2012) © 2012 Ye et alen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.contributor.mitauthorLamming, Dudley
dc.contributor.mitauthorSabatini, David
dc.relation.journalFrontiers in Geneticsen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2018-07-03T18:36:20Z
dspace.orderedauthorsYe, Lan; Varamini, Behzad; Lamming, Dudley W.; Sabatini, David M.; Baur, Joseph A.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-0079-4467
dc.identifier.orcidhttps://orcid.org/0000-0002-1446-7256
mit.licensePUBLISHER_CCen_US


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