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. 2012 Mar 30;335(6076):1638-43.
doi: 10.1126/science.1215135.

Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity

Dudley W Lamming  1 , 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

Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity

Dudley W Lamming et al. Science. .

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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Figures

Figure 1
Figure 1
Rapamycin-induced insulin resistance is independent of hepatic mTORC1. A-F) Glucose infusion rate (A), rate of disappearance of glucose from the circulation (B), hepatic gluconeogenesis (C) and insulin responsiveness (D), as well as glucose uptake by white adipose tissue (E) and skeletal muscle (F) were determined during a hyperinsulinemic-euglycemic clamp in mice treated with 2 mg/kg/day rapamycin or vehicle control for two weeks. (Each dot represents a single animal, n = 13 vehicle-treated mice, 11 rapamycin-treated mice, * = P < 1×10-5, Student’s t-test; # = P < 0.045 by Brown-Mood k-sample median test.) G) Serum glucose and insulin concentration in rapamycin-treated mice during fasting and after re-feeding for 4 hours (* = P < 0.02). H) Phosphorylation of the mTORC1 substrate S6K1 T389 and subsequent phosphorylation of S6 in the livers of rapamycin-treated mice. I,J) Glucose tolerance with or without rapamycin treatment in mice lacking hepatic Raptor (* = P < 0.05, # = P < 0.06 for rapamycin treated groups vs. untreated). All bars indicate mean and SEM.
Figure 2
Figure 2
Disruption of mTORC2 in vivo after chronic rapamycin treatment. A, B) Effects of rapamycin on phosphorylation of PKCα, Akt, and the SGK substrate NDRG1 in liver in response to re-feeding (A) or insulin (B) after an overnight fast. C, D) Effects of rapamycin on phosphorylation of PKCα and Akt in response to re-feeding in white adipose tissue (C) and muscle (D). E-G) Effects of rapamycin on the integrity of mTORC1 and mTORC2. mTOR was immunoprecipitated from liver (E), skeletal muscle (F), and white adipose tissue (G), followed by immunoblotting for Raptor and Rictor (subunits of mTORC1 and mTORC2, respectively).
Figure 3
Figure 3
Regulation of glucose homeostasis by mTORC2. A) Glucose tolerance of Alb-Cre RictorLoxP/LoxP mice (* = P< 0.002). B) Pyruvate tolerance of Alb-Cre RictorloxP/loxP mice (* = P < 0.03). C) Effect of rapamycin on glucose tolerance of mice with whole-body deletion of Rictor fasted for 6 hr (* = P < 0.008 for all groups vs. wt). D-I) Glucose infusion rate (D), rate of disappearance of glucose from the circulation (E), hepatic gluconeogenesis (F) and insulin responsiveness (G), and glucose uptake by white adipose tissue (H) and skeletal muscle (I) were determined during a hyperinsulinemic-euglycemic clamp in tamoxifen-treated UbiquitinC-CreERT2 RictorloxP/loxP mice fasted for 6 hr (n = 8 RictorloxP/loxP, 7 UBC-Cre RictorloxP/loxP, ** = P < 0.008; * = P <0.05). All bars indicate mean and SEM.
Figure 4
Figure 4
Depletion of mTOR and mLST8 uncouples longevity from decreased glucose tolerance. A, B) Kaplan-Meier plots showing lifespans of female (A) and male (B) mice heterozygous for components of the mTOR signaling pathway. C, D) Lifespans of female (C) and male (D) mtor+/- mlst8+/- mice. Wild-type curves are repeated for comparison. E) Quantification of phosphorylated proteins in female wild-type and mtor+/- mlst8+/- livers after an overnight fast and 45 minutes of refeeding (n = 13 wild-type vs. 13 mtor+/- mlst8+/- female mice, * = P < 0.03). F) Q-PCR of mRNA levels for PEPCK and G6Pase in the livers of young female wild type and mtor+/- mlst8+/- mice (* = P < 0.03). G, H) Immunoprecipitation of mTOR complexes reveals preferential loss of Raptor association in mtor+/- mlst8+/- female mice (* = P < 0.02). All bars indicate mean and SEM.
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