Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo

Maximilian Kleinert; Lykke Sylow; Daniel J. Fazakerley; James R. Krycer; Kristen C Thomas; Anne-Julie Oxbøll; Andreas Børsting Jordy; Thomas Elbenhardt Jensen; Guang Yang; Peter Schjerling; Bente Kiens; David E James; Markus A Ruegg; Erik Richter

doi:10.1060/j.molmet.2014.06.004

Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo

Maximilian Kleinert, Lykke Sylow, Daniel J. Fazakerley, James R. Krycer, Kristen C Thomas, Anne-Julie Oxbøll, Andreas Børsting Jordy, Thomas Elbenhardt Jensen, Guang Yang, Peter Schjerling, Bente Kiens, David E James, Markus A Ruegg, Erik Richter

The August Krogh Section for Molecular Physiology

49 Citations (Scopus)

Abstract

The effect of acute inhibition of both mTORC1 and mTORC2 on metabolism is unknown. A single injection of the mTOR kinase inhibitor, AZD8055, induced a transient, yet marked increase in fat oxidation and insulin resistance in mice, whereas the mTORC1 inhibitor rapamycin had no effect. AZD8055, but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose homeostasis in part by blocking muscle mTORC2, indicating its importance in muscle metabolism in vivo.

Original language	English
Journal	Molecular Metabolism
Volume	3
Issue number	6
Pages (from-to)	630-641
Number of pages	11
ISSN	2212-8778
DOIs	https://doi.org/10.1060/j.molmet.2014.06.004
Publication status	Published - Sept 2014

Access to Document

10.1060/j.molmet.2014.06.004

http://www.sciencedirect.com/science/article/pii/S221287781400115X#

Cite this

Kleinert, M., Sylow, L., Fazakerley, D. J., Krycer, J. R., Thomas, K. C., Oxbøll, A-J., Jordy, A. B., Jensen, T. E., Yang, G., Schjerling, P., Kiens, B., James, D. E., Ruegg, M. A., & Richter, E. (2014). Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo. Molecular Metabolism, 3(6), 630-641. https://doi.org/10.1060/j.molmet.2014.06.004

@article{98df88512f3c41fa9d215c310febff7a,

title = "Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo",

abstract = "The effect of acute inhibition of both mTORC1 and mTORC2 on metabolism is unknown. A single injection of the mTOR kinase inhibitor, AZD8055, induced a transient, yet marked increase in fat oxidation and insulin resistance in mice, whereas the mTORC1 inhibitor rapamycin had no effect. AZD8055, but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose homeostasis in part by blocking muscle mTORC2, indicating its importance in muscle metabolism in vivo.",

author = "Maximilian Kleinert and Lykke Sylow and Fazakerley, {Daniel J.} and Krycer, {James R.} and Thomas, {Kristen C} and Anne-Julie Oxb{\o}ll and Jordy, {Andreas B{\o}rsting} and Jensen, {Thomas Elbenhardt} and Guang Yang and Peter Schjerling and Bente Kiens and James, {David E} and Ruegg, {Markus A} and Erik Richter",

note = "CURIS 2014 NEXS 256",

year = "2014",

month = sep,

doi = "10.1060/j.molmet.2014.06.004",

language = "English",

volume = "3",

pages = "630--641",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

number = "6",

}

TY - JOUR

T1 - Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo

AU - Kleinert, Maximilian

AU - Sylow, Lykke

AU - Fazakerley, Daniel J.

AU - Krycer, James R.

AU - Thomas, Kristen C

AU - Oxbøll, Anne-Julie

AU - Jordy, Andreas Børsting

AU - Jensen, Thomas Elbenhardt

AU - Yang, Guang

AU - Schjerling, Peter

AU - Kiens, Bente

AU - James, David E

AU - Ruegg, Markus A

AU - Richter, Erik

N1 - CURIS 2014 NEXS 256

PY - 2014/9

Y1 - 2014/9

N2 - The effect of acute inhibition of both mTORC1 and mTORC2 on metabolism is unknown. A single injection of the mTOR kinase inhibitor, AZD8055, induced a transient, yet marked increase in fat oxidation and insulin resistance in mice, whereas the mTORC1 inhibitor rapamycin had no effect. AZD8055, but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose homeostasis in part by blocking muscle mTORC2, indicating its importance in muscle metabolism in vivo.

AB - The effect of acute inhibition of both mTORC1 and mTORC2 on metabolism is unknown. A single injection of the mTOR kinase inhibitor, AZD8055, induced a transient, yet marked increase in fat oxidation and insulin resistance in mice, whereas the mTORC1 inhibitor rapamycin had no effect. AZD8055, but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose homeostasis in part by blocking muscle mTORC2, indicating its importance in muscle metabolism in vivo.

U2 - 10.1060/j.molmet.2014.06.004

DO - 10.1060/j.molmet.2014.06.004

M3 - Journal article

SN - 2212-8778

VL - 3

SP - 630

EP - 641

JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 6

ER -

Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo

Abstract

Access to Document

Fingerprint

Cite this