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Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

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 al...

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Autores principales: Warren, Eleanor C., Dooves, Stephanie, Lugarà, Eleonora, Damstra-Oddy, Joseph, Schaf, Judith, Heine, Vivi M., Walker, Mathew C., Williams, Robin S. B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519326/
https://www.ncbi.nlm.nih.gov/pubmed/32879008
http://dx.doi.org/10.1073/pnas.2008980117
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author Warren, Eleanor C.
Dooves, Stephanie
Lugarà, Eleonora
Damstra-Oddy, Joseph
Schaf, Judith
Heine, Vivi M.
Walker, Mathew C.
Williams, Robin S. B.
author_facet Warren, Eleanor C.
Dooves, Stephanie
Lugarà, Eleonora
Damstra-Oddy, Joseph
Schaf, Judith
Heine, Vivi M.
Walker, Mathew C.
Williams, Robin S. B.
author_sort Warren, Eleanor C.
collection PubMed
description 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.
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spelling pubmed-75193262020-10-07 Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling Warren, Eleanor C. Dooves, Stephanie Lugarà, Eleonora Damstra-Oddy, Joseph Schaf, Judith Heine, Vivi M. Walker, Mathew C. Williams, Robin S. B. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2020-09-22 2020-09-02 /pmc/articles/PMC7519326/ /pubmed/32879008 http://dx.doi.org/10.1073/pnas.2008980117 Text en Copyright © 2020 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Warren, Eleanor C.
Dooves, Stephanie
Lugarà, Eleonora
Damstra-Oddy, Joseph
Schaf, Judith
Heine, Vivi M.
Walker, Mathew C.
Williams, Robin S. B.
Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling
title Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling
title_full Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling
title_fullStr Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling
title_full_unstemmed Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling
title_short Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling
title_sort decanoic acid inhibits mtorc1 activity independent of glucose and insulin signaling
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519326/
https://www.ncbi.nlm.nih.gov/pubmed/32879008
http://dx.doi.org/10.1073/pnas.2008980117
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