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

Cell Metab. 2019 Dec 3;30(6):1141-1151.e5. doi: 10.1016/j.cmet.2019.08.021. Epub 2019 Sep 19.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Gastrointestinal Microbiome / physiology
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Indoles / pharmacology
  • Insulin Resistance
  • Metabolic Syndrome / metabolism*
  • Methylamines / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Oxygenases / antagonists & inhibitors
  • eIF-2 Kinase / metabolism*

Substances

  • Indoles
  • Methylamines
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • EIF2AK3 protein, human
  • PERK kinase
  • eIF-2 Kinase
  • trimethyloxamine
  • 3,3'-diindolylmethane