Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction

Sifan Chen; Ayana Henderson; Michael C. Petriello; Kymberleigh A. Romano; Mary Gearing; Ji Miao; Mareike Schell; Walter J. Sandoval-Espinola; Jiahui Tao; Bingdong Sha; Mark Graham; Rosanne Crooke; Andre Kleinridders; Emily P. Balskus; Federico E. Rey; Andrew J. Morris; Sudha B. Biddinger

doi:10.1016/j.cmet.2019.08.021

Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction

Sifan Chen, Ayana Henderson, Michael C. Petriello, Kymberleigh A. Romano, Mary Gearing, Ji Miao, Mareike Schell, Walter J. Sandoval-Espinola, Jiahui Tao, Bingdong Sha, Mark Graham, Rosanne Crooke, Andre Kleinridders, Emily P. Balskus, Federico E. Rey, Andrew J. Morris, Sudha B. Biddinger

Internal Medicine

Research output: Contribution to journal › Article › peer-review

192 Scopus citations

Abstract

The gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) is increased by insulin resistance and associated with several sequelae of metabolic syndrome in humans, including cardiovascular, renal, and neurodegenerative disease. The mechanism by which TMAO promotes disease is unclear. We now reveal the endoplasmic reticulum stress kinase PERK (EIF2AK3) as a receptor for TMAO: TMAO binds to PERK at physiologically relevant concentrations; selectively activates the PERK branch of the unfolded protein response; and induces the transcription factor FoxO1, a key driver of metabolic disease, in a PERK-dependent manner. Furthermore, interventions to reduce TMAO, either by manipulation of the gut microbiota or by inhibition of the TMAO synthesizing enzyme, flavin-containing monooxygenase 3, can reduce PERK activation and FoxO1 levels in the liver. Taken together, these data suggest TMAO and PERK may be central to the pathogenesis of the metabolic syndrome.

Original language	English
Pages (from-to)	1141-1151.e5
Journal	Cell Metabolism
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2019.08.021
State	Published - Dec 3 2019

Bibliographical note

Funding Information:
These studies were supported by R01HL109650 (S.B.B.), the American Heart Association (Established Investigator Award to S.B.B.), and R00DK100539 (J.M.). M.S. and A.K. were supported by a grant from the German Ministry of Education and Research (BMBF) and the State of Brandenburg ( DZD grant 82DZD00302 ).

Publisher Copyright:
© 2019

Keywords

EIF2AK3
FoxO1
PERK
diabetes
endoplasmic reticulum stress
insulin signaling
metabolomics
trimethylamine N-oxide

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2019.08.021

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Chen, S., Henderson, A., Petriello, M. C., Romano, K. A., Gearing, M., Miao, J., Schell, M., Sandoval-Espinola, W. J., Tao, J., Sha, B., Graham, M., Crooke, R., Kleinridders, A., Balskus, E. P., Rey, F. E., Morris, A. J., & Biddinger, S. B. (2019). Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell Metabolism, 30(6), 1141-1151.e5. https://doi.org/10.1016/j.cmet.2019.08.021

@article{e67e860010d84752831bf6535f933b3d,

title = "Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction",

abstract = "The gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) is increased by insulin resistance and associated with several sequelae of metabolic syndrome in humans, including cardiovascular, renal, and neurodegenerative disease. The mechanism by which TMAO promotes disease is unclear. We now reveal the endoplasmic reticulum stress kinase PERK (EIF2AK3) as a receptor for TMAO: TMAO binds to PERK at physiologically relevant concentrations; selectively activates the PERK branch of the unfolded protein response; and induces the transcription factor FoxO1, a key driver of metabolic disease, in a PERK-dependent manner. Furthermore, interventions to reduce TMAO, either by manipulation of the gut microbiota or by inhibition of the TMAO synthesizing enzyme, flavin-containing monooxygenase 3, can reduce PERK activation and FoxO1 levels in the liver. Taken together, these data suggest TMAO and PERK may be central to the pathogenesis of the metabolic syndrome.",

keywords = "EIF2AK3, FoxO1, PERK, diabetes, endoplasmic reticulum stress, insulin signaling, metabolomics, trimethylamine N-oxide",

author = "Sifan Chen and Ayana Henderson and Petriello, {Michael C.} and Romano, {Kymberleigh A.} and Mary Gearing and Ji Miao and Mareike Schell and Sandoval-Espinola, {Walter J.} and Jiahui Tao and Bingdong Sha and Mark Graham and Rosanne Crooke and Andre Kleinridders and Balskus, {Emily P.} and Rey, {Federico E.} and Morris, {Andrew J.} and Biddinger, {Sudha B.}",

note = "Funding Information: These studies were supported by R01HL109650 (S.B.B.), the American Heart Association (Established Investigator Award to S.B.B.), and R00DK100539 (J.M.). M.S. and A.K. were supported by a grant from the German Ministry of Education and Research (BMBF) and the State of Brandenburg ( DZD grant 82DZD00302 ). Publisher Copyright: {\textcopyright} 2019",

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doi = "10.1016/j.cmet.2019.08.021",

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Chen, S, Henderson, A, Petriello, MC, Romano, KA, Gearing, M, Miao, J, Schell, M, Sandoval-Espinola, WJ, Tao, J, Sha, B, Graham, M, Crooke, R, Kleinridders, A, Balskus, EP, Rey, FE, Morris, AJ & Biddinger, SB 2019, 'Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction', Cell Metabolism, vol. 30, no. 6, pp. 1141-1151.e5. https://doi.org/10.1016/j.cmet.2019.08.021

TY - JOUR

T1 - Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction

AU - Chen, Sifan

AU - Henderson, Ayana

AU - Petriello, Michael C.

AU - Romano, Kymberleigh A.

AU - Gearing, Mary

AU - Miao, Ji

AU - Schell, Mareike

AU - Sandoval-Espinola, Walter J.

AU - Tao, Jiahui

AU - Sha, Bingdong

AU - Graham, Mark

AU - Crooke, Rosanne

AU - Kleinridders, Andre

AU - Balskus, Emily P.

AU - Rey, Federico E.

AU - Morris, Andrew J.

AU - Biddinger, Sudha B.

N1 - Funding Information: These studies were supported by R01HL109650 (S.B.B.), the American Heart Association (Established Investigator Award to S.B.B.), and R00DK100539 (J.M.). M.S. and A.K. were supported by a grant from the German Ministry of Education and Research (BMBF) and the State of Brandenburg ( DZD grant 82DZD00302 ). Publisher Copyright: © 2019

PY - 2019/12/3

Y1 - 2019/12/3

N2 - The gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) is increased by insulin resistance and associated with several sequelae of metabolic syndrome in humans, including cardiovascular, renal, and neurodegenerative disease. The mechanism by which TMAO promotes disease is unclear. We now reveal the endoplasmic reticulum stress kinase PERK (EIF2AK3) as a receptor for TMAO: TMAO binds to PERK at physiologically relevant concentrations; selectively activates the PERK branch of the unfolded protein response; and induces the transcription factor FoxO1, a key driver of metabolic disease, in a PERK-dependent manner. Furthermore, interventions to reduce TMAO, either by manipulation of the gut microbiota or by inhibition of the TMAO synthesizing enzyme, flavin-containing monooxygenase 3, can reduce PERK activation and FoxO1 levels in the liver. Taken together, these data suggest TMAO and PERK may be central to the pathogenesis of the metabolic syndrome.

AB - The gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) is increased by insulin resistance and associated with several sequelae of metabolic syndrome in humans, including cardiovascular, renal, and neurodegenerative disease. The mechanism by which TMAO promotes disease is unclear. We now reveal the endoplasmic reticulum stress kinase PERK (EIF2AK3) as a receptor for TMAO: TMAO binds to PERK at physiologically relevant concentrations; selectively activates the PERK branch of the unfolded protein response; and induces the transcription factor FoxO1, a key driver of metabolic disease, in a PERK-dependent manner. Furthermore, interventions to reduce TMAO, either by manipulation of the gut microbiota or by inhibition of the TMAO synthesizing enzyme, flavin-containing monooxygenase 3, can reduce PERK activation and FoxO1 levels in the liver. Taken together, these data suggest TMAO and PERK may be central to the pathogenesis of the metabolic syndrome.

KW - EIF2AK3

KW - FoxO1

KW - PERK

KW - diabetes

KW - endoplasmic reticulum stress

KW - insulin signaling

KW - metabolomics

KW - trimethylamine N-oxide

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U2 - 10.1016/j.cmet.2019.08.021

DO - 10.1016/j.cmet.2019.08.021

M3 - Article

C2 - 31543404

AN - SCOPUS:85075446550

SN - 1550-4131

VL - 30

SP - 1141-1151.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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