期刊
NATURE MEDICINE
卷 24, 期 3, 页码 292-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4481
关键词
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资金
- Deutsche Forschungsgemeinschaft Research Fellowship [BA 4925/1-1]
- Canadian Institutes of Health Research fellowship
- University Medical Center Hamburg-Eppendorf MD/PhD program fellowship
- Barth Syndrome Foundation
- US National Institutes of Health (NIH) through the Laser Biomedical Research Center [P41-EB015871, 5-U54-CA151884]
- National Science Foundation [ECCS-1449291]
- Massachusetts Institute of Technology through the Institute for Soldier Nanotechnologies [W911NF13-D-0001]
- Boehringer Ingelheim Fonds
- European Molecular Biology Organization Long-term Fellowship
- NIH [R01DK077097, R01DK102898, P30DK036836, T32DK007260, F32DK102320, K01DK111714]
- Pew Foundation
- Harvard University
- Servier
- Directorate For Engineering
- Div Of Electrical, Commun & Cyber Sys [1449291] Funding Source: National Science Foundation
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 PA28 alpha 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.
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