2. Academic Validation
  3. Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

  • Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23617-23625. doi: 10.1073/pnas.2008980117.
Eleanor C Warren 1,  Stephanie Dooves 2,  Eleonora Lugarà 3,  Joseph Damstra-Oddy 1,  Judith Schaf 1,  Vivi M Heine 2 4,  Mathew C Walker 3,  Robin S B Williams 5
Affiliations

Affiliations

  • 1 Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom.
  • 2 Department of Child and Youth Psychiatry, Amsterdam Universitair Medische Centra, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
  • 3 Clinical and Experimental Epilepsy UCL, Queen Square Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
  • 4 Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
  • 5 Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom; robin.williams@rhul.ac.uk.
PMID: 32879008 DOI: 10.1073/pnas.2008980117
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.

Keywords

Dictyostelium discoideum; decanoic acid; epilepsy; mTOR; tuberous sclerosis complex.

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