Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity
Author(s)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.; Sabatini, David M.; Baur, Joseph A.; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
American Association for the Advancement of Science
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.
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