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

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.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Chaudhuri R,Krycer JR,Fazakerley DJ,Fisher-Wellman KH,Su Z,Hoehn KL,Yang JYH,Kuncic Z,Vafaee F,James DE

doi

10.1038/s41598-018-20104-x

subject

Has Abstract

pub_date

2018-01-29 00:00:00

pages

1774

issue

1

issn

2045-2322

pii

10.1038/s41598-018-20104-x

journal_volume

8

pub_type

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