Deficiency in ROS-sensing nuclear factor erythroid 2-like 2 causes altered glucose and lipid homeostasis following exercise training

Am J Physiol Cell Physiol. 2020 Feb 1;318(2):C337-C345. doi: 10.1152/ajpcell.00426.2019. Epub 2019 Nov 27.


Oxidative stress induced by acute exercise may regulate exercise training-induced adaptations that improve metabolic health. One of the central transcription regulatory targets of reactive oxygen species (ROS) is Nrf2 (nuclear factor erythroid-derived 2-like 2, or NFE2L2). Here, we investigated whether global deficiency of Nrf2 in mice would impact exercise training-induced changes in glucose and lipid homeostasis. We report that following 6 wk of treadmill exercise training, Nrf2-deficient mice have elevated fasting plasma triglycerides and free fatty acids and higher blood glucose levels following a meal despite having a similar fat mass to wild-type controls. This impaired glucose homeostasis appears to be related to reduced insulin sensitivity primarily in adipose and liver tissue, and although a clear mechanism was not evident, Nrf2-deficient mice had increased markers of hepatic oxidative stress and stress-related kinase activation in white adipose tissue (WAT) without overt inflammation alteration in WAT or modulation of hepatic and WAT fibroblast growth factor 21 gene expression. Our results suggest that Nrf2 facilitates exercise training-induced improvements in glucose homeostasis; however, further research is required to determine whether this occurs through direct regulation of exercise adaptations or via the maintenance of redox balance during training.

Keywords: NFE2L2; exercise; insulin resistance; metabolism; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Fatty Acids, Nonesterified / blood
  • Fibroblasts / metabolism
  • Gene Expression Regulation / physiology
  • Glucose / metabolism*
  • Homeostasis / physiology*
  • Inflammation / blood
  • Inflammation / metabolism
  • Insulin / metabolism
  • Lipids / blood*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / physiology
  • Physical Conditioning, Animal / physiology*
  • Reactive Oxygen Species / metabolism*
  • Transcription, Genetic / physiology
  • Triglycerides / blood


  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Insulin
  • Lipids
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Triglycerides
  • Glucose