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

Research output: Contribution to journalArticlepeer-review

114 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 languageEnglish
Pages (from-to)1141-1151.e5
JournalCell Metabolism
Volume30
Issue number6
DOIs
StatePublished - 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

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