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Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice

Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefo...

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Autores principales: Keung, Wendy, Ussher, John R., Jaswal, Jagdip S., Raubenheimer, Monique, Lam, Victoria H.M., Wagg, Cory S., Lopaschuk, Gary D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581198/
https://www.ncbi.nlm.nih.gov/pubmed/23139350
http://dx.doi.org/10.2337/db12-0259
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author Keung, Wendy
Ussher, John R.
Jaswal, Jagdip S.
Raubenheimer, Monique
Lam, Victoria H.M.
Wagg, Cory S.
Lopaschuk, Gary D.
author_facet Keung, Wendy
Ussher, John R.
Jaswal, Jagdip S.
Raubenheimer, Monique
Lam, Victoria H.M.
Wagg, Cory S.
Lopaschuk, Gary D.
author_sort Keung, Wendy
collection PubMed
description Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefore investigated what effect inhibition of mitochondrial fatty acid uptake has on whole-body glucose tolerance and insulin sensitivity in obese insulin-resistant mice. C57BL/6 mice were fed a high-fat diet (60% calories from fat) for 12 weeks to develop insulin resistance. Subsequent treatment of mice for 4 weeks with the carnitine palmitoyltransferase-1 inhibitor, oxfenicine (150 mg/kg i.p. daily), resulted in improved whole-body glucose tolerance and insulin sensitivity. Exercise capacity was increased in oxfenicine-treated mice, which was accompanied by an increased respiratory exchange ratio. In the gastrocnemius muscle, oxfenicine increased pyruvate dehydrogenase activity, membrane GLUT4 content, and insulin-stimulated Akt phosphorylation. Intramyocellular levels of lipid intermediates, including ceramide, long-chain acyl CoA, and diacylglycerol, were also decreased. Our results demonstrate that inhibition of mitochondrial fatty acid uptake improves insulin sensitivity in diet-induced obese mice. This is associated with increased carbohydrate utilization and improved insulin signaling in the skeletal muscle, suggestive of an operating Randle Cycle in muscle.
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spelling pubmed-35811982014-03-01 Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice Keung, Wendy Ussher, John R. Jaswal, Jagdip S. Raubenheimer, Monique Lam, Victoria H.M. Wagg, Cory S. Lopaschuk, Gary D. Diabetes Metabolism Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefore investigated what effect inhibition of mitochondrial fatty acid uptake has on whole-body glucose tolerance and insulin sensitivity in obese insulin-resistant mice. C57BL/6 mice were fed a high-fat diet (60% calories from fat) for 12 weeks to develop insulin resistance. Subsequent treatment of mice for 4 weeks with the carnitine palmitoyltransferase-1 inhibitor, oxfenicine (150 mg/kg i.p. daily), resulted in improved whole-body glucose tolerance and insulin sensitivity. Exercise capacity was increased in oxfenicine-treated mice, which was accompanied by an increased respiratory exchange ratio. In the gastrocnemius muscle, oxfenicine increased pyruvate dehydrogenase activity, membrane GLUT4 content, and insulin-stimulated Akt phosphorylation. Intramyocellular levels of lipid intermediates, including ceramide, long-chain acyl CoA, and diacylglycerol, were also decreased. Our results demonstrate that inhibition of mitochondrial fatty acid uptake improves insulin sensitivity in diet-induced obese mice. This is associated with increased carbohydrate utilization and improved insulin signaling in the skeletal muscle, suggestive of an operating Randle Cycle in muscle. American Diabetes Association 2013-03 2013-02-14 /pmc/articles/PMC3581198/ /pubmed/23139350 http://dx.doi.org/10.2337/db12-0259 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Metabolism
Keung, Wendy
Ussher, John R.
Jaswal, Jagdip S.
Raubenheimer, Monique
Lam, Victoria H.M.
Wagg, Cory S.
Lopaschuk, Gary D.
Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice
title Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice
title_full Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice
title_fullStr Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice
title_full_unstemmed Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice
title_short Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice
title_sort inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581198/
https://www.ncbi.nlm.nih.gov/pubmed/23139350
http://dx.doi.org/10.2337/db12-0259
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