title: Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Dudley W
authors.initials: DW
authors.lastname: Lamming
authors.forename: Lan
authors.initials: L
authors.lastname: Ye
authors.forename: Pekka
authors.initials: P
authors.lastname: Katajisto
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Goncalves
authors.forename: Maki
authors.initials: M
authors.lastname: Saitoh
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Stevens
authors.forename: James G
authors.initials: JG
authors.lastname: Davis
authors.forename: Adam B
authors.initials: AB
authors.lastname: Salmon
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.forename: David A
authors.initials: DA
authors.lastname: Guertin
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006706:Homeostasis; D007328:Insulin / Q000008:administration & dosage / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008136:Longevity; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D046912:Multiprotein Complexes; D011506:Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus