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Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance
BACKGROUND: Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short-term preclinical animal studies. However, the long-term eff...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190034/ https://www.ncbi.nlm.nih.gov/pubmed/25309812 http://dx.doi.org/10.4172/2155-6156.1000361 |
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author | Kim, Teayoun He, Lan Johnson, Maria S. Li, Yan Zeng, Ling Ding, Yishu Long, Qinqiang Moore, John F. Sharer, Jon D. Nagy, Tim R. Young, Martin E. Wood, Philip A. Yang, Qinglin |
author_facet | Kim, Teayoun He, Lan Johnson, Maria S. Li, Yan Zeng, Ling Ding, Yishu Long, Qinqiang Moore, John F. Sharer, Jon D. Nagy, Tim R. Young, Martin E. Wood, Philip A. Yang, Qinglin |
author_sort | Kim, Teayoun |
collection | PubMed |
description | BACKGROUND: Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short-term preclinical animal studies. However, the long-term effects of treatment remain unclear and potential non-specific effects of these CPT1 inhibitors hamper in-depth understanding of the potential molecular mechanisms involved. METHODS: We investigated the effects of restricting the activity of the muscle isoform CPT1b in mice using heterozygous CPT1b deficient (Cpt1b(+/−)) and Wild Type (WT) mice fed with a High Fat Diet (HFD) for 22 weeks. Insulin sensitivity was assessed using Glucose Tolerance Test (GTT), insulin tolerance test and hyperinsulinemic euglycemic clamps. We also examined body weight/composition, tissue and systemic metabolism/energetic status, lipid profile, transcript analysis, and changes in insulin signaling pathways. RESULTS: We found that Cpt1b(+/−) mice were protected from HFD-induced insulin resistance compared to WT littermates. Cpt1b(+/−) mice exhibited elevated whole body glucose disposal rate and skeletal muscle glucose uptake. Furthermore, Cpt1b(+/−) skeletal muscle showed diminished ex vivo palmitate oxidative capacity by ~40% and augmented glucose oxidation capacity by ~50% without overt change in whole body energy metabolism. HFD feeding Cpt1b(+/−) but not WT mice exhibited well-maintained insulin signaling in skeletal muscle, heart, and liver. CONCLUSION: The present study on a genetic model of CPT1b restriction supports the concept that partial CPT1b inhibition is a potential therapeutic strategy. |
format | Online Article Text |
id | pubmed-4190034 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-41900342014-10-08 Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance Kim, Teayoun He, Lan Johnson, Maria S. Li, Yan Zeng, Ling Ding, Yishu Long, Qinqiang Moore, John F. Sharer, Jon D. Nagy, Tim R. Young, Martin E. Wood, Philip A. Yang, Qinglin J Diabetes Metab Article BACKGROUND: Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short-term preclinical animal studies. However, the long-term effects of treatment remain unclear and potential non-specific effects of these CPT1 inhibitors hamper in-depth understanding of the potential molecular mechanisms involved. METHODS: We investigated the effects of restricting the activity of the muscle isoform CPT1b in mice using heterozygous CPT1b deficient (Cpt1b(+/−)) and Wild Type (WT) mice fed with a High Fat Diet (HFD) for 22 weeks. Insulin sensitivity was assessed using Glucose Tolerance Test (GTT), insulin tolerance test and hyperinsulinemic euglycemic clamps. We also examined body weight/composition, tissue and systemic metabolism/energetic status, lipid profile, transcript analysis, and changes in insulin signaling pathways. RESULTS: We found that Cpt1b(+/−) mice were protected from HFD-induced insulin resistance compared to WT littermates. Cpt1b(+/−) mice exhibited elevated whole body glucose disposal rate and skeletal muscle glucose uptake. Furthermore, Cpt1b(+/−) skeletal muscle showed diminished ex vivo palmitate oxidative capacity by ~40% and augmented glucose oxidation capacity by ~50% without overt change in whole body energy metabolism. HFD feeding Cpt1b(+/−) but not WT mice exhibited well-maintained insulin signaling in skeletal muscle, heart, and liver. CONCLUSION: The present study on a genetic model of CPT1b restriction supports the concept that partial CPT1b inhibition is a potential therapeutic strategy. 2014-04-25 2014-04-01 /pmc/articles/PMC4190034/ /pubmed/25309812 http://dx.doi.org/10.4172/2155-6156.1000361 Text en Copyright: © 2014 Kim T, et al. http://creativecommons.org/licenses/by/3.0/ 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 credited. |
spellingShingle | Article Kim, Teayoun He, Lan Johnson, Maria S. Li, Yan Zeng, Ling Ding, Yishu Long, Qinqiang Moore, John F. Sharer, Jon D. Nagy, Tim R. Young, Martin E. Wood, Philip A. Yang, Qinglin Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance |
title | Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance |
title_full | Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance |
title_fullStr | Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance |
title_full_unstemmed | Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance |
title_short | Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance |
title_sort | carnitine palmitoyltransferase 1b deficiency protects mice from diet-induced insulin resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190034/ https://www.ncbi.nlm.nih.gov/pubmed/25309812 http://dx.doi.org/10.4172/2155-6156.1000361 |
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