Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity

Dudley W. Lamming, Lan Ye, Pekka Katajisto, Marcus D. Goncalves, Maki Saitoh, Deanna M. Stevens, James G. Davis, Adam B. Salmon, Arlan Richardson, Rexford S. Ahima, David A. Guertin, David M. Sabatini, Joseph A. Baur

Research output: Contribution to journalArticlepeer-review

714 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1638-1643
Number of pages6
JournalScience
Volume335
Issue number6076
DOIs
StatePublished - Mar 30 2012

ASJC Scopus subject areas

  • General

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