dc.contributor.author | Ye, Lan | |
dc.contributor.author | Varamini, Behzad | |
dc.contributor.author | Baur, Joseph A. | |
dc.contributor.author | Sabatini, David | |
dc.contributor.author | Lamming, Dudley W. | |
dc.date.accessioned | 2018-07-03T19:13:33Z | |
dc.date.available | 2018-07-03T19:13:33Z | |
dc.date.issued | 2012-09 | |
dc.identifier.issn | 1664-8021 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/116773 | |
dc.description.abstract | Rapamycin, 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.publisher | Frontiers Research Foundation | en_US |
dc.relation.isversionof | http://dx.doi.org/10.3389/fgene.2012.00177 | en_US |
dc.rights | Creative Commons Attribution 4.0 International License | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.source | Frontiers | en_US |
dc.title | Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2 | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Ye, 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 al | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biology | en_US |
dc.contributor.department | Koch Institute for Integrative Cancer Research at MIT | en_US |
dc.contributor.mitauthor | Lamming, Dudley | |
dc.contributor.mitauthor | Sabatini, David | |
dc.relation.journal | Frontiers in Genetics | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2018-07-03T18:36:20Z | |
dspace.orderedauthors | Ye, Lan; Varamini, Behzad; Lamming, Dudley W.; Sabatini, David M.; Baur, Joseph A. | en_US |
dspace.embargo.terms | N | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-0079-4467 | |
dc.identifier.orcid | https://orcid.org/0000-0002-1446-7256 | |
mit.license | PUBLISHER_CC | en_US |