Cargando…

Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart

Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought t...

Descripción completa

Detalles Bibliográficos
Autores principales: Crewe, Clair, Kinter, Michael, Szweda, Luke I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792029/
https://www.ncbi.nlm.nih.gov/pubmed/24116221
http://dx.doi.org/10.1371/journal.pone.0077280
_version_ 1782286787965616128
author Crewe, Clair
Kinter, Michael
Szweda, Luke I.
author_facet Crewe, Clair
Kinter, Michael
Szweda, Luke I.
author_sort Crewe, Clair
collection PubMed
description Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production.
format Online
Article
Text
id pubmed-3792029
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-37920292013-10-10 Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart Crewe, Clair Kinter, Michael Szweda, Luke I. PLoS One Research Article Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production. Public Library of Science 2013-10-07 /pmc/articles/PMC3792029/ /pubmed/24116221 http://dx.doi.org/10.1371/journal.pone.0077280 Text en © 2013 Crewe et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Crewe, Clair
Kinter, Michael
Szweda, Luke I.
Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart
title Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart
title_full Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart
title_fullStr Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart
title_full_unstemmed Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart
title_short Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart
title_sort rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heart
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792029/
https://www.ncbi.nlm.nih.gov/pubmed/24116221
http://dx.doi.org/10.1371/journal.pone.0077280
work_keys_str_mv AT creweclair rapidinhibitionofpyruvatedehydrogenaseaninitiatingeventinhighdietaryfatinducedlossofmetabolicflexibilityintheheart
AT kintermichael rapidinhibitionofpyruvatedehydrogenaseaninitiatingeventinhighdietaryfatinducedlossofmetabolicflexibilityintheheart
AT szwedalukei rapidinhibitionofpyruvatedehydrogenaseaninitiatingeventinhighdietaryfatinducedlossofmetabolicflexibilityintheheart