Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

Eleanor C. Warren, Stephanie Dooves, Eleonora Lugarà, Joseph Damstra-Oddy, Judith Schaf, Vivi M. Heine, Mathew C. Walker, Robin S.B. Williams

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Here, we determined whether mTORC1 signaling is also a target for decanoic acid, a key component of the medium-chain triglyceride (MCT) ketogenic diet. Using a tractable model system, Dictyostelium, we show that decanoic acid can decrease mTORC1 activity, under conditions of constant glucose and in the absence of insulin, measured by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). We determine that this effect of decanoic acid is dependent on a ubiquitin regulatory X domain-containing protein, mediating inhibition of a conserved Dictyostelium AAA ATPase, p97, a homolog of the human transitional endoplasmic reticulum ATPase (VCP/p97) protein. We then demonstrate that decanoic acid decreases mTORC1 activity in the absence of insulin and under high-glucose conditions in ex vivo rat hippocampus and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Our data therefore indicate that dietary decanoic acid may provide a new therapeutic approach to down-regulate mTORC1 signaling.

Original languageEnglish
Pages (from-to)23617-23625
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number38
DOIs
Publication statusPublished - 22 Sep 2020

Keywords

  • decanoic acid
  • Dictyostelium discoideum
  • epilepsy
  • mTOR
  • tuberous sclerosis complex

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