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Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity

Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and thus are an important cell type to maintain proper metabolic health. While the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptat...

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Autores principales: Bartelt, Alexander, Widenmaier, Scott B., Schlein, Christian, Johann, Kornelia, Goncalves, Renata L. S., Eguchi, Kosei, Fischer, Alexander W., Parlakgül, Günes, Snyder, Nicole A., Nguyen, Truc B., Bruns, Oliver T., Franke, Daniel, Bawendi, Moungi G., Lynes, Matthew D., Leiria, Luiz O., Tseng, Yu-Hua, Inouye, Karen E., Arruda, Ana Paula, Hotamisligil, Gökhan S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839993/
https://www.ncbi.nlm.nih.gov/pubmed/29400713
http://dx.doi.org/10.1038/nm.4481
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author Bartelt, Alexander
Widenmaier, Scott B.
Schlein, Christian
Johann, Kornelia
Goncalves, Renata L. S.
Eguchi, Kosei
Fischer, Alexander W.
Parlakgül, Günes
Snyder, Nicole A.
Nguyen, Truc B.
Bruns, Oliver T.
Franke, Daniel
Bawendi, Moungi G.
Lynes, Matthew D.
Leiria, Luiz O.
Tseng, Yu-Hua
Inouye, Karen E.
Arruda, Ana Paula
Hotamisligil, Gökhan S.
author_facet Bartelt, Alexander
Widenmaier, Scott B.
Schlein, Christian
Johann, Kornelia
Goncalves, Renata L. S.
Eguchi, Kosei
Fischer, Alexander W.
Parlakgül, Günes
Snyder, Nicole A.
Nguyen, Truc B.
Bruns, Oliver T.
Franke, Daniel
Bawendi, Moungi G.
Lynes, Matthew D.
Leiria, Luiz O.
Tseng, Yu-Hua
Inouye, Karen E.
Arruda, Ana Paula
Hotamisligil, Gökhan S.
author_sort Bartelt, Alexander
collection PubMed
description Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and thus are an important cell type to maintain proper metabolic health. While the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER in adipocytes to metabolic challenges 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 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 induced Nrf1 in BAT to increase proteasomal activity, and that this was 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 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 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.
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spelling pubmed-58399932018-08-05 Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity Bartelt, Alexander Widenmaier, Scott B. Schlein, Christian Johann, Kornelia Goncalves, Renata L. S. Eguchi, Kosei Fischer, Alexander W. Parlakgül, Günes Snyder, Nicole A. Nguyen, Truc B. Bruns, Oliver T. Franke, Daniel Bawendi, Moungi G. Lynes, Matthew D. Leiria, Luiz O. Tseng, Yu-Hua Inouye, Karen E. Arruda, Ana Paula Hotamisligil, Gökhan S. Nat Med Article Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and thus are an important cell type to maintain proper metabolic health. While the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER in adipocytes to metabolic challenges 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 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 induced Nrf1 in BAT to increase proteasomal activity, and that this was 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 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 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. 2018-02-05 2018-03 /pmc/articles/PMC5839993/ /pubmed/29400713 http://dx.doi.org/10.1038/nm.4481 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Bartelt, Alexander
Widenmaier, Scott B.
Schlein, Christian
Johann, Kornelia
Goncalves, Renata L. S.
Eguchi, Kosei
Fischer, Alexander W.
Parlakgül, Günes
Snyder, Nicole A.
Nguyen, Truc B.
Bruns, Oliver T.
Franke, Daniel
Bawendi, Moungi G.
Lynes, Matthew D.
Leiria, Luiz O.
Tseng, Yu-Hua
Inouye, Karen E.
Arruda, Ana Paula
Hotamisligil, Gökhan S.
Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity
title Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity
title_full Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity
title_fullStr Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity
title_full_unstemmed Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity
title_short Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity
title_sort brown adipose tissue thermogenic adaptation requires nrf1-mediated proteasomal activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839993/
https://www.ncbi.nlm.nih.gov/pubmed/29400713
http://dx.doi.org/10.1038/nm.4481
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