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The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes
Insulin resistance is a major risk factor for metabolic diseases such as Type 2 diabetes. Although the underlying mechanisms of insulin resistance remain elusive, oxidative stress is a unifying driver by which numerous extrinsic signals and cellular stresses trigger insulin resistance. Consequently,...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789081/ https://www.ncbi.nlm.nih.gov/pubmed/29379070 http://dx.doi.org/10.1038/s41598-018-20104-x |
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author | Chaudhuri, Rima Krycer, James R. Fazakerley, Daniel J. Fisher-Wellman, Kelsey H. Su, Zhiduan Hoehn, Kyle L. Yang, Jean Yee Hwa Kuncic, Zdenka Vafaee, Fatemeh James, David E. |
author_facet | Chaudhuri, Rima Krycer, James R. Fazakerley, Daniel J. Fisher-Wellman, Kelsey H. Su, Zhiduan Hoehn, Kyle L. Yang, Jean Yee Hwa Kuncic, Zdenka Vafaee, Fatemeh James, David E. |
author_sort | Chaudhuri, Rima |
collection | PubMed |
description | Insulin resistance is a major risk factor for metabolic diseases such as Type 2 diabetes. Although the underlying mechanisms of insulin resistance remain elusive, oxidative stress is a unifying driver by which numerous extrinsic signals and cellular stresses trigger insulin resistance. Consequently, we sought to understand the cellular response to oxidative stress and its role in insulin resistance. Using cultured 3T3-L1 adipocytes, we established a model of physiologically-derived oxidative stress by inhibiting the cycling of glutathione and thioredoxin, which induced insulin resistance as measured by impaired insulin-stimulated 2-deoxyglucose uptake. Using time-resolved transcriptomics, we found > 2000 genes differentially-expressed over 24 hours, with specific metabolic and signalling pathways enriched at different times. We explored this coordination using a knowledge-based hierarchical-clustering approach to generate a temporal transcriptional cascade and identify key transcription factors responding to oxidative stress. This response shared many similarities with changes observed in distinct insulin resistance models. However, an anti-oxidant reversed insulin resistance phenotypically but not transcriptionally, implying that the transcriptional response to oxidative stress is insufficient for insulin resistance. This suggests that the primary site by which oxidative stress impairs insulin action occurs post-transcriptionally, warranting a multi-level ‘trans-omic’ approach when studying time-resolved responses to cellular perturbations. |
format | Online Article Text |
id | pubmed-5789081 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57890812018-02-08 The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes Chaudhuri, Rima Krycer, James R. Fazakerley, Daniel J. Fisher-Wellman, Kelsey H. Su, Zhiduan Hoehn, Kyle L. Yang, Jean Yee Hwa Kuncic, Zdenka Vafaee, Fatemeh James, David E. Sci Rep Article Insulin resistance is a major risk factor for metabolic diseases such as Type 2 diabetes. Although the underlying mechanisms of insulin resistance remain elusive, oxidative stress is a unifying driver by which numerous extrinsic signals and cellular stresses trigger insulin resistance. Consequently, we sought to understand the cellular response to oxidative stress and its role in insulin resistance. Using cultured 3T3-L1 adipocytes, we established a model of physiologically-derived oxidative stress by inhibiting the cycling of glutathione and thioredoxin, which induced insulin resistance as measured by impaired insulin-stimulated 2-deoxyglucose uptake. Using time-resolved transcriptomics, we found > 2000 genes differentially-expressed over 24 hours, with specific metabolic and signalling pathways enriched at different times. We explored this coordination using a knowledge-based hierarchical-clustering approach to generate a temporal transcriptional cascade and identify key transcription factors responding to oxidative stress. This response shared many similarities with changes observed in distinct insulin resistance models. However, an anti-oxidant reversed insulin resistance phenotypically but not transcriptionally, implying that the transcriptional response to oxidative stress is insufficient for insulin resistance. This suggests that the primary site by which oxidative stress impairs insulin action occurs post-transcriptionally, warranting a multi-level ‘trans-omic’ approach when studying time-resolved responses to cellular perturbations. Nature Publishing Group UK 2018-01-29 /pmc/articles/PMC5789081/ /pubmed/29379070 http://dx.doi.org/10.1038/s41598-018-20104-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Chaudhuri, Rima Krycer, James R. Fazakerley, Daniel J. Fisher-Wellman, Kelsey H. Su, Zhiduan Hoehn, Kyle L. Yang, Jean Yee Hwa Kuncic, Zdenka Vafaee, Fatemeh James, David E. The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes |
title | The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes |
title_full | The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes |
title_fullStr | The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes |
title_full_unstemmed | The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes |
title_short | The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes |
title_sort | transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789081/ https://www.ncbi.nlm.nih.gov/pubmed/29379070 http://dx.doi.org/10.1038/s41598-018-20104-x |
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