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Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding

BACKGROUND: Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria. Treatments with CPT1 inhibitors protect against insulin resistance in short-term preclinical animal studies. We recently reported that mice with muscle isofo...

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Autores principales: Kim, Teayoun, Moore, John F, Sharer, Jon D, Yang, Kevin, Wood, Philip A, Yang, Qinglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286342/
https://www.ncbi.nlm.nih.gov/pubmed/25580367
http://dx.doi.org/10.4172/2155-6156.1000401
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author Kim, Teayoun
Moore, John F
Sharer, Jon D
Yang, Kevin
Wood, Philip A
Yang, Qinglin
author_facet Kim, Teayoun
Moore, John F
Sharer, Jon D
Yang, Kevin
Wood, Philip A
Yang, Qinglin
author_sort Kim, Teayoun
collection PubMed
description BACKGROUND: Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria. Treatments with CPT1 inhibitors protect against insulin resistance in short-term preclinical animal studies. We recently reported that mice with muscle isoform CPT1b deficiency demonstrated improved insulin sensitivity when fed a High Fat-Diet (HFD) for up to 5 months. In this follow up study, we further investigated whether the insulin sensitizing effects of partial CPT1b deficiency could be maintained under a prolonged HFD feeding condition. METHODS: We investigated the effects of CPT1b deficiency on HFD-induced insulin resistance using heterozygous CPT1b deficient (Cpt1b(+/−)) mice compared with Wild Type (WT) mice fed a HFD for a prolonged period of time (7 months). We assessed insulin sensitivity using hyperinsulinemic-euglycemic clamps. We also examined body composition, skeletal muscle lipid profile, and changes in the insulin signaling pathways of skeletal muscle, liver, and adipose tissue. RESULTS: We found that Cpt1b(+/−) mice became severely insulin resistant after 7 months of HFD feeding. Cpt1b(+/−) mice exhibited a substantially reduced glucose infusion rate and skeletal muscle glucose uptake. While Cpt1b(+/−) mice maintained a slower weight gain with less fat mass than WT mice, accumulation of lipid intermediates became evident in the muscle of Cpt1b(+/−) but not WT mice after 7 months of HFD feeding. Insulin signaling was impaired in the Cpt1b(+/−) as compared to the WT muscles. CONCLUSION: Partial CPT1b deficiency, mimicking CPT1b inhibition, may lead to impaired insulin signaling and insulin sensitivity under a prolonged HFD feeding condition. Therefore, further studies on the potential detrimental effects of prolonged therapy with CPT1 inhibition are necessary in the development of this potential therapeutic strategy.
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spelling pubmed-42863422015-01-07 Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding Kim, Teayoun Moore, John F Sharer, Jon D Yang, Kevin Wood, Philip A Yang, Qinglin J Diabetes Metab Article BACKGROUND: Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria. Treatments with CPT1 inhibitors protect against insulin resistance in short-term preclinical animal studies. We recently reported that mice with muscle isoform CPT1b deficiency demonstrated improved insulin sensitivity when fed a High Fat-Diet (HFD) for up to 5 months. In this follow up study, we further investigated whether the insulin sensitizing effects of partial CPT1b deficiency could be maintained under a prolonged HFD feeding condition. METHODS: We investigated the effects of CPT1b deficiency on HFD-induced insulin resistance using heterozygous CPT1b deficient (Cpt1b(+/−)) mice compared with Wild Type (WT) mice fed a HFD for a prolonged period of time (7 months). We assessed insulin sensitivity using hyperinsulinemic-euglycemic clamps. We also examined body composition, skeletal muscle lipid profile, and changes in the insulin signaling pathways of skeletal muscle, liver, and adipose tissue. RESULTS: We found that Cpt1b(+/−) mice became severely insulin resistant after 7 months of HFD feeding. Cpt1b(+/−) mice exhibited a substantially reduced glucose infusion rate and skeletal muscle glucose uptake. While Cpt1b(+/−) mice maintained a slower weight gain with less fat mass than WT mice, accumulation of lipid intermediates became evident in the muscle of Cpt1b(+/−) but not WT mice after 7 months of HFD feeding. Insulin signaling was impaired in the Cpt1b(+/−) as compared to the WT muscles. CONCLUSION: Partial CPT1b deficiency, mimicking CPT1b inhibition, may lead to impaired insulin signaling and insulin sensitivity under a prolonged HFD feeding condition. Therefore, further studies on the potential detrimental effects of prolonged therapy with CPT1 inhibition are necessary in the development of this potential therapeutic strategy. 2014-07-04 2014 /pmc/articles/PMC4286342/ /pubmed/25580367 http://dx.doi.org/10.4172/2155-6156.1000401 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
Moore, John F
Sharer, Jon D
Yang, Kevin
Wood, Philip A
Yang, Qinglin
Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding
title Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding
title_full Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding
title_fullStr Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding
title_full_unstemmed Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding
title_short Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding
title_sort carnitine palmitoyltransferase 1b deficient mice develop severe insulin resistance after prolonged high fat diet feeding
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286342/
https://www.ncbi.nlm.nih.gov/pubmed/25580367
http://dx.doi.org/10.4172/2155-6156.1000401
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