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Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo
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 no...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142396/ https://www.ncbi.nlm.nih.gov/pubmed/25161886 http://dx.doi.org/10.1016/j.molmet.2014.06.004 |
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author | Kleinert, Maximilian Sylow, Lykke Fazakerley, Daniel J. Krycer, James R. Thomas, Kristen C. Oxbøll, Anne-Julie Jordy, Andreas B. Jensen, Thomas E. Yang, Guang Schjerling, Peter Kiens, Bente James, David E. Ruegg, Markus A. Richter, Erik A. |
author_facet | Kleinert, Maximilian Sylow, Lykke Fazakerley, Daniel J. Krycer, James R. Thomas, Kristen C. Oxbøll, Anne-Julie Jordy, Andreas B. Jensen, Thomas E. Yang, Guang Schjerling, Peter Kiens, Bente James, David E. Ruegg, Markus A. Richter, Erik A. |
author_sort | Kleinert, Maximilian |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4142396 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-41423962014-08-26 Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo Kleinert, Maximilian Sylow, Lykke Fazakerley, Daniel J. Krycer, James R. Thomas, Kristen C. Oxbøll, Anne-Julie Jordy, Andreas B. Jensen, Thomas E. Yang, Guang Schjerling, Peter Kiens, Bente James, David E. Ruegg, Markus A. Richter, Erik A. Mol Metab Original Article 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. Elsevier 2014-06-27 /pmc/articles/PMC4142396/ /pubmed/25161886 http://dx.doi.org/10.1016/j.molmet.2014.06.004 Text en © 2014 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). |
spellingShingle | Original Article Kleinert, Maximilian Sylow, Lykke Fazakerley, Daniel J. Krycer, James R. Thomas, Kristen C. Oxbøll, Anne-Julie Jordy, Andreas B. Jensen, Thomas E. Yang, Guang Schjerling, Peter Kiens, Bente James, David E. Ruegg, Markus A. Richter, Erik A. Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo |
title | Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo |
title_full | Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo |
title_fullStr | Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo |
title_full_unstemmed | Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo |
title_short | Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo |
title_sort | acute mtor inhibition induces insulin resistance and alters substrate utilization in vivo |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142396/ https://www.ncbi.nlm.nih.gov/pubmed/25161886 http://dx.doi.org/10.1016/j.molmet.2014.06.004 |
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