Authors: Lamming DW; Ye L; Katajisto P; Goncalves MD; Saitoh M; Stevens DM; Davis JG; Salmon AB; Richardson A; Ahima RS; Guertin DA; Sabatini DM; Baur JA
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.
Keywords: Adipose Tissue, White/metabolism; Animals; Carrier Proteins/genetics/metabolism; Female; Gluconeogenesis; Glucose/metabolism; Glucose Clamp Technique; Homeostasis; Insulin/administration & dosage/blood; *Insulin Resistance; Liver/metabolism; *Longevity; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal/metabolism; Phosphorylation; Proteins/antagonists & inhibitors/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Signal Transduction; Sirolimus/*pharmacology; TOR Serine-Threonine Kinases/genetics/metabolism|
Journal: Science (New York, N.Y.) Volume: 335 Issue: 6076 Pages: 1638-43 Date: March 31, 2012 PMID: 22461615 |
Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA (2012) Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science (New York, N.Y.) 335: 1638-43.
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