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Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse

Cytochrome P450 4x1 (Cyp4x1) is expressed at very high levels in the brain but the function of this protein is unknown. It has been hypothesised to regulate metabolism of fatty acids and to affect the activity of endocannabinoid signalling systems, which are known to influence appetite and energy me...

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Autores principales: Kharkwal, Himanshu, Batool, Farhat, Koentgen, Frank, Bell, David R., Kendall, David A., Ebling, Francis J. P., Duce, Ian R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724839/
https://www.ncbi.nlm.nih.gov/pubmed/29227996
http://dx.doi.org/10.1371/journal.pone.0187959
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author Kharkwal, Himanshu
Batool, Farhat
Koentgen, Frank
Bell, David R.
Kendall, David A.
Ebling, Francis J. P.
Duce, Ian R.
author_facet Kharkwal, Himanshu
Batool, Farhat
Koentgen, Frank
Bell, David R.
Kendall, David A.
Ebling, Francis J. P.
Duce, Ian R.
author_sort Kharkwal, Himanshu
collection PubMed
description Cytochrome P450 4x1 (Cyp4x1) is expressed at very high levels in the brain but the function of this protein is unknown. It has been hypothesised to regulate metabolism of fatty acids and to affect the activity of endocannabinoid signalling systems, which are known to influence appetite and energy metabolism. The objective of the present investigation was to determine the impact of Cyp4x1 on body weight and energy metabolism by developing a line of transgenic Cyp4x1-knock out mice. Mice were developed with a global knock-out of the gene; the full-length RNA was undetectable, and mice were viable and fertile. Both male and female Cyp4x1-knock out mice gained significantly more body weight on normal lab chow diet compared to control flox mice on the same genetic background. At necropsy, Cyp4x1-knock out male mice had significantly greater intra-abdominal fat deposits (P<0.01), and enlarged adipocytes. Metabolic rate and locomotor activity as inferred from VO(2) measures and crossing of infrared beams in metabolic cages were not significantly affected by the mutation in either gender. The respiratory exchange ratio was significantly decreased in male knock out mice (P<0.05), suggesting a greater degree of fat oxidation, consistent with their higher adiposity. When mice were maintained on a high fat diet, VO(2) was significantly decreased in both male and female Cyp4x1-knock out mice. We conclude that the Cyp4x1-knock out mouse strain demonstrates a mildly obese phenotype, consistent with the view that cytochrome P450 4x1 plays a role in regulating fat metabolism.
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spelling pubmed-57248392017-12-15 Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse Kharkwal, Himanshu Batool, Farhat Koentgen, Frank Bell, David R. Kendall, David A. Ebling, Francis J. P. Duce, Ian R. PLoS One Research Article Cytochrome P450 4x1 (Cyp4x1) is expressed at very high levels in the brain but the function of this protein is unknown. It has been hypothesised to regulate metabolism of fatty acids and to affect the activity of endocannabinoid signalling systems, which are known to influence appetite and energy metabolism. The objective of the present investigation was to determine the impact of Cyp4x1 on body weight and energy metabolism by developing a line of transgenic Cyp4x1-knock out mice. Mice were developed with a global knock-out of the gene; the full-length RNA was undetectable, and mice were viable and fertile. Both male and female Cyp4x1-knock out mice gained significantly more body weight on normal lab chow diet compared to control flox mice on the same genetic background. At necropsy, Cyp4x1-knock out male mice had significantly greater intra-abdominal fat deposits (P<0.01), and enlarged adipocytes. Metabolic rate and locomotor activity as inferred from VO(2) measures and crossing of infrared beams in metabolic cages were not significantly affected by the mutation in either gender. The respiratory exchange ratio was significantly decreased in male knock out mice (P<0.05), suggesting a greater degree of fat oxidation, consistent with their higher adiposity. When mice were maintained on a high fat diet, VO(2) was significantly decreased in both male and female Cyp4x1-knock out mice. We conclude that the Cyp4x1-knock out mouse strain demonstrates a mildly obese phenotype, consistent with the view that cytochrome P450 4x1 plays a role in regulating fat metabolism. Public Library of Science 2017-12-11 /pmc/articles/PMC5724839/ /pubmed/29227996 http://dx.doi.org/10.1371/journal.pone.0187959 Text en © 2017 Kharkwal 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kharkwal, Himanshu
Batool, Farhat
Koentgen, Frank
Bell, David R.
Kendall, David A.
Ebling, Francis J. P.
Duce, Ian R.
Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse
title Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse
title_full Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse
title_fullStr Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse
title_full_unstemmed Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse
title_short Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse
title_sort generation and phenotypic characterisation of a cytochrome p450 4x1 knockout mouse
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724839/
https://www.ncbi.nlm.nih.gov/pubmed/29227996
http://dx.doi.org/10.1371/journal.pone.0187959
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