Format

Send to

Choose Destination
Sci Rep. 2018 Jan 29;8(1):1774. doi: 10.1038/s41598-018-20104-x.

The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes.

Author information

1
Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia.
2
School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
3
Duke Molecular Physiology Institute, Duke University, Durham, NC, 27701, USA.
4
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia.
5
School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, 2006, Australia.
6
School of Physics and Australian Institute for Nanoscale Science and Technology, The University of Sydney, Sydney, NSW, 2006, Australia.
7
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia. f.vafaee@unsw.edu.au.
8
Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia. david.james@sydney.edu.au.
9
School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia. david.james@sydney.edu.au.
10
Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia. david.james@sydney.edu.au.

Abstract

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.

PMID:
29379070
PMCID:
PMC5789081
DOI:
10.1038/s41598-018-20104-x
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center