Unbound MEDLINE

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.

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  • 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

    Institution

    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

    Source

    Science (New York, N.Y.) 335:6076 2012 Mar 30 pg 1638-43

    MeSH

    Adipose Tissue, White
    Animals
    Carrier Proteins
    Female
    Gluconeogenesis
    Glucose
    Glucose Clamp Technique
    Homeostasis
    Insulin
    Insulin Resistance
    Liver
    Longevity
    Male
    Mice
    Mice, Inbred C57BL
    Muscle, Skeletal
    Phosphorylation
    Proteins
    Proto-Oncogene Proteins c-akt
    Signal Transduction
    Sirolimus
    TOR Serine-Threonine Kinases

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22461615