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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2020
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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. |
format | Online Article Text |
id | pubmed-7519326 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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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