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Science 335 (6076): 1638-1643

Copyright © 2012 by the American Association for the Advancement of Science

Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity

Dudley W. Lamming,1,2,3,4,5,{dagger} Lan Ye,6,{dagger} Pekka Katajisto,1,2,3,4,5 Marcus D. Goncalves,7 Maki Saitoh,1,2,3,4,5 Deanna M. Stevens,1,2,3,4,5 James G. Davis,6 Adam B. Salmon,8 Arlan Richardson,8 Rexford S. Ahima,7 David A. Guertin,1,2,3,4,5,* David M. Sabatini,1,2,3,4,5,{ddagger} Joseph A. Baur6,{ddagger}

Abstract: 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.

1 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
2 Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
3 Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA.
4 Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA 02142, USA.
5 The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
6 Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
7 Department of Medicine, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8 The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.

* Present address: University of Massachusetts Medical School, Worcester, MA 01655, USA.

{dagger} These authors contributed equally to this work

{ddagger} To whom correspondence should be addressed. E-mail: baur{at}mail.med.upenn.edu (J.A.B.); sabatini{at}wi.mit.edu (D.M.S.)

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