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ID 115105
Title Alternative
ISR-DEPENDENT METABOLIC REGULATION
Author
Nomura, Akitoshi The University of Tokushima
Ogura, Atsushi The University of Tokushima
Takehana, Kenji Ajinomoto Pharmaceuticals Company
Kitahara, Yoshihiro Ajinomoto Pharmaceuticals Company
Takahara, Kazuna The University of Tokushima KAKEN Search Researchers
Tsugawa, Kazue The University of Tokushima
Miyamoto, Chinobu The University of Tokushima
Miura, Naoko The University of Tokushima
Sato, Ryosuke The University of Tokushima KAKEN Search Researchers
Harding, Heather P. University of Cambridge
Ron, David University of Cambridge
Keywords
ER stress
ATF4
glutathione
obesity
small molecule
Content Type
Journal Article
Description
The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation‐dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand‐activated skeletal muscle–specific derivative of the eIF2α protein kinase R‐like ER kinase revealed the expected up‐regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small‐molecule ISR activator that promoted Fgf21 expression in cell‐based screens and by implication of the ISR‐inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell‐autonomous proteostasis and amino acid metabolism, but also affects non‐cell‐autonomous metabolic regulation by induced expression of a potent myokine.—Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle‐specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21‐mediated non‐cell‐autonomous energy metabolism.
Journal Title
The FASEB Journal
ISSN
15306860
08926638
NCID
AA1066874X
AA12037502
Publisher
Federation of American Societies for Experimental Biology|John Wiley & Sons
Volume
30
Issue
2
Start Page
798
End Page
812
Published Date
2015-10-20
Rights
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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DOI (Published Version)
URL ( Publisher's Version )
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language
eng
TextVersion
Publisher
departments
Institute of Advanced Medical Sciences
University Hospital
Medical Sciences