Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity

Nat Med. 2018 Mar;24(3):292-303. doi: 10.1038/nm.4481. Epub 2018 Feb 5.


Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induces Nrf1 in BAT to increase proteasomal activity and that this is crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown-adipocyte-specific deletion of Nfe2l1 (Nrf1) resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or by treatment with the proteasome activator PA28α in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acclimatization / genetics
  • Acclimatization / physiology
  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Cold Temperature
  • Endoplasmic Reticulum / genetics*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / genetics
  • Gene Deletion
  • Homeostasis
  • Humans
  • Inflammation / genetics
  • Inflammation / physiopathology
  • Insulin Resistance / genetics
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Models, Animal
  • NF-E2-Related Factor 1 / genetics*
  • Obesity / genetics*
  • Obesity / physiopathology
  • Proteasome Endopeptidase Complex / genetics*
  • Proteasome Endopeptidase Complex / metabolism
  • Thermogenesis / genetics


  • NF-E2-Related Factor 1
  • Nfe2L1 protein, mouse
  • Proteasome Endopeptidase Complex
  • Psme1 protein, mouse