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

Kleinert, Maximilian and Sylow, Lykke and Fazakerley, Daniel J. and Krycer, James R. and Thomas, Kristen C. and Oxbøll, Anne-Julie and Jordy, Andreas B. and Jensen, Thomas E. and Yang, Guang and Schjerling, Peter and Kiens, Bente and James, David E. and Ruegg, Markus A. and Richter, Erik A.. (2014) Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo. Molecular Metabolism, 3 (6). pp. 630-641.

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Official URL: http://edoc.unibas.ch/dok/A6319252

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
e-ISSN:2212-8778
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:15 Nov 2017 12:49
Deposited On:05 Dec 2014 09:45

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