Rapamycin-induced Insulin Resistance is Mediated by MTORC2 Loss and Uncoupled from Longevity

Overview

Journal Science

Specialty Science

Date 2012 Mar 31

PMID 22461615

Citations 657

Authors

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

Affiliations

Soon will be listed here.

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.

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