Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

J Biol Chem. 2016 Apr 1;291(14):7754-66. doi: 10.1074/jbc.M115.673756. Epub 2016 Feb 3.


The NRF2 (also known as NFE2L2) transcription factor is a critical regulator of genes involved in defense against oxidative stress. Previous studies suggest thatNrf2plays a role in adipogenesisin vitro, and deletion of theNrf2gene protects against diet-induced obesity in mice. Here, we demonstrate that resistance to diet-induced obesity inNrf2(-/-)mice is associated with a 20-30% increase in energy expenditure. Analysis of bioenergetics revealed thatNrf2(-/-)white adipose tissues exhibit greater oxygen consumption. White adipose tissue showed a >2-fold increase inUcp1gene expression. Oxygen consumption is also increased nearly 2.5-fold inNrf2-deficient fibroblasts. Oxidative stress induced by glucose oxidase resulted in increasedUcp1expression. Conversely, antioxidant chemicals (such asN-acetylcysteine and Mn(III)tetrakis(4-benzoic acid)porphyrin chloride) and SB203580 (a known suppressor ofUcp1expression) decreasedUcp1and oxygen consumption inNrf2-deficient fibroblasts. These findings suggest that increasing oxidative stress by limitingNrf2function in white adipocytes may be a novel means to modulate energy balance as a treatment of obesity and related clinical disorders.

Keywords: adipose tissue; antioxidant; oxidative stress; reactive oxygen species (ROS); uncoupling protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipogenesis*
  • Animals
  • Diet / adverse effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Free Radical Scavengers / pharmacology
  • Gene Expression Regulation*
  • Ion Channels / biosynthesis*
  • Ion Channels / genetics
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / biosynthesis*
  • Mitochondrial Proteins / genetics
  • NF-E2-Related Factor 2 / deficiency*
  • Obesity / chemically induced
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Oxidative Stress*
  • Oxygen Consumption / drug effects
  • Uncoupling Protein 1


  • Free Radical Scavengers
  • Ion Channels
  • Mitochondrial Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • UCP1 protein, human
  • Ucp1 protein, mouse
  • Uncoupling Protein 1