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

Research output: Contribution to journalArticle


  • 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

External Institution(s)

  • Sun Yat-Sen University
  • Harvard University
  • University of Wisconsin-Madison
  • German Institute of Human Nutrition Potsdam-Rehbruecke
  • German Center for Diabetes Research (DZD e.V.)
  • University of Alabama at Birmingham
  • Ionis Pharmaceuticals
  • University of Kentucky
  • Department of Veterans Affairs


Original languageEnglish (US)
Pages (from-to)1141-1151.e5
JournalCell metabolism
Issue number6
StatusPublished - Dec 3 2019


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.

    Research areas

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

Citation formats


Chen, S., Henderson, A., Petriello, M. C., Romano, K. A., Gearing, M., Miao, J., ... Biddinger, S. B. (2019). Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell metabolism, 30(6), 1141-1151.e5.


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.