Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity.

Nat Med
Authors
Keywords
Abstract

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.

Year of Publication
2018
Journal
Nat Med
Volume
24
Issue
3
Pages
292-303
Date Published
2018 03
ISSN
1546-170X
DOI
10.1038/nm.4481
PubMed ID
29400713
PubMed Central ID
PMC5839993
Links
Grant list
R01 EB000244 / EB / NIBIB NIH HHS / United States
U54 CA151884 / CA / NCI NIH HHS / United States
R01 DK102898 / DK / NIDDK NIH HHS / United States
T32 DK007260 / DK / NIDDK NIH HHS / United States
P30 DK036836 / DK / NIDDK NIH HHS / United States
R01 DK077097 / DK / NIDDK NIH HHS / United States
P41 EB015871 / EB / NIBIB NIH HHS / United States
K01 DK111714 / DK / NIDDK NIH HHS / United States
F32 DK102320 / DK / NIDDK NIH HHS / United States