TY - JOUR
T1 - Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity
AU - Lamming, Dudley W.
AU - Ye, Lan
AU - Katajisto, Pekka
AU - Goncalves, Marcus D.
AU - Saitoh, Maki
AU - Stevens, Deanna M.
AU - Davis, James G.
AU - Salmon, Adam B.
AU - Richardson, Arlan
AU - Ahima, Rexford S.
AU - Guertin, David A.
AU - Sabatini, David M.
AU - Baur, Joseph A.
PY - 2012/3/30
Y1 - 2012/3/30
N2 - 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.
AB - 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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U2 - 10.1126/science.1215135
DO - 10.1126/science.1215135
M3 - Article
C2 - 22461615
AN - SCOPUS:84859117806
SN - 0036-8075
VL - 335
SP - 1638
EP - 1643
JO - Science
JF - Science
IS - 6076
ER -