Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity
Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapam...
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/85837 https://orcid.org/0000-0002-0079-4467 https://orcid.org/0000-0002-1446-7256 |
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| author | Lamming, Dudley W. Ye, Lan Katajisto, Pekka Goncalves, Marcus D. Saitoh, Maki Stevens, Deanna M. Davis, James G. Salmon, Adam B. Richardson, Arlan Ahima, Rexford S. Guertin, David A. Baur, Joseph A. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Lamming, Dudley W. Ye, Lan Katajisto, Pekka Goncalves, Marcus D. Saitoh, Maki Stevens, Deanna M. Davis, James G. Salmon, Adam B. Richardson, Arlan Ahima, Rexford S. Guertin, David A. Baur, Joseph A. Sabatini, David |
| author_sort | Lamming, Dudley W. |
| collection | MIT |
| description | Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo. |
| first_indexed | 2024-09-23T13:11:36Z |
| format | Article |
| id | mit-1721.1/85837 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:11:36Z |
| publishDate | 2014 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | mit-1721.1/858372022-10-01T13:38:57Z Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity Lamming, Dudley W. Ye, Lan Katajisto, Pekka Goncalves, Marcus D. Saitoh, Maki Stevens, Deanna M. Davis, James G. Salmon, Adam B. Richardson, Arlan Ahima, Rexford S. Guertin, David A. Baur, Joseph A. Sabatini, David Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Lamming, Dudley W. Katajisto, Pekka Saitoh, Maki Stevens, Deanna M. Guertin, David A. Sabatini, David M. Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo. American Federation for Aging Research University of Pennsylvania. Institute on Aging (Bingham Trust Pilot Award) National Institutes of Health (U.S.) (NIH (CA129105)) Starr Foundation David H. Koch Institute for Integrative Cancer Research at MIT (Frontier Research Program award) Ellison Medical Foundation Damon Runyon Cancer Research Foundation (Fellowship) National Institutes of Health (U.S.). (Ruth L. Kirschstein National Research Service Award (1F32AG032833-01A1)) American Heart Association (postdoctoral fellowship (7600031)) Academy of Finland 2014-03-19T19:54:11Z 2014-03-19T19:54:11Z 2012-03 2011-10 Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/85837 Lamming, D. W., L. Ye, P. Katajisto, M. D. Goncalves, M. Saitoh, D. M. Stevens, J. G. Davis, et al. “Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity.” Science 335, no. 6076 (March 29, 2012): 1638-1643. https://orcid.org/0000-0002-0079-4467 https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1126/science.1215135 Science Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Association for the Advancement of Science PMC |
| spellingShingle | Lamming, Dudley W. Ye, Lan Katajisto, Pekka Goncalves, Marcus D. Saitoh, Maki Stevens, Deanna M. Davis, James G. Salmon, Adam B. Richardson, Arlan Ahima, Rexford S. Guertin, David A. Baur, Joseph A. Sabatini, David Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity |
| title | Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity |
| title_full | Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity |
| title_fullStr | Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity |
| title_full_unstemmed | Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity |
| title_short | Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity |
| title_sort | rapamycin induced insulin resistance is mediated by mtorc2 loss and uncoupled from longevity |
| url | http://hdl.handle.net/1721.1/85837 https://orcid.org/0000-0002-0079-4467 https://orcid.org/0000-0002-1446-7256 |
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