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New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity

BACKGROUND: According to the World Health Organization (WHO) there is a pandemic of obesity with approximately 300 million people being obese. Typically, human obesity has a polygenetic causation. Neutral endopeptidase (NEP), also known as neprilysin, is considered to be one of the key enzymes in th...

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Autores principales: Becker, Matthias, Siems, Wolf-Eberhard, Kluge, Reinhart, Gembardt, Florian, Schultheiss, Heinz-Peter, Schirner, Michael, Walther, Thomas
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940827/
https://www.ncbi.nlm.nih.gov/pubmed/20862277
http://dx.doi.org/10.1371/journal.pone.0012793
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author Becker, Matthias
Siems, Wolf-Eberhard
Kluge, Reinhart
Gembardt, Florian
Schultheiss, Heinz-Peter
Schirner, Michael
Walther, Thomas
author_facet Becker, Matthias
Siems, Wolf-Eberhard
Kluge, Reinhart
Gembardt, Florian
Schultheiss, Heinz-Peter
Schirner, Michael
Walther, Thomas
author_sort Becker, Matthias
collection PubMed
description BACKGROUND: According to the World Health Organization (WHO) there is a pandemic of obesity with approximately 300 million people being obese. Typically, human obesity has a polygenetic causation. Neutral endopeptidase (NEP), also known as neprilysin, is considered to be one of the key enzymes in the metabolism of many active peptide hormones. METHODOLOGY/PRINCIPAL FINDINGS: An incidental observation in NEP-deficient mice was a late-onset excessive gain in body weight exclusively from a ubiquitous accumulation of fat tissue. In accord with polygenetic human obesity, mice were characterized by deregulation of lipid metabolism, higher blood glucose levels, with impaired glucose tolerance. The key role of NEP in determining body mass was confirmed by the use of the NEP inhibitor candoxatril in wild-type mice that increased body weight due to increased food intake. This is a peripheral and not a central NEP action on the switch for appetite control, since candoxatril cannot cross the blood-brain barrier. Furthermore, we demonstrated that inhibition of NEP in mice with cachexia delayed rapid body weight loss. Thus, lack in NEP activity, genetically or pharmacologically, leads to a gain in body fat. CONCLUSIONS/SIGNIFICANCE: In the present study, we have identified NEP to be a crucial player in the development of obesity. NEP-deficient mice start to become obese under a normocaloric diet in an age of 6–7 months and thus are an ideal model for the typical human late-onset obesity. Therefore, the described obesity model is an ideal tool for research on development, molecular mechanisms, diagnosis, and therapy of the pandemic obesity.
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spelling pubmed-29408272010-09-22 New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity Becker, Matthias Siems, Wolf-Eberhard Kluge, Reinhart Gembardt, Florian Schultheiss, Heinz-Peter Schirner, Michael Walther, Thomas PLoS One Research Article BACKGROUND: According to the World Health Organization (WHO) there is a pandemic of obesity with approximately 300 million people being obese. Typically, human obesity has a polygenetic causation. Neutral endopeptidase (NEP), also known as neprilysin, is considered to be one of the key enzymes in the metabolism of many active peptide hormones. METHODOLOGY/PRINCIPAL FINDINGS: An incidental observation in NEP-deficient mice was a late-onset excessive gain in body weight exclusively from a ubiquitous accumulation of fat tissue. In accord with polygenetic human obesity, mice were characterized by deregulation of lipid metabolism, higher blood glucose levels, with impaired glucose tolerance. The key role of NEP in determining body mass was confirmed by the use of the NEP inhibitor candoxatril in wild-type mice that increased body weight due to increased food intake. This is a peripheral and not a central NEP action on the switch for appetite control, since candoxatril cannot cross the blood-brain barrier. Furthermore, we demonstrated that inhibition of NEP in mice with cachexia delayed rapid body weight loss. Thus, lack in NEP activity, genetically or pharmacologically, leads to a gain in body fat. CONCLUSIONS/SIGNIFICANCE: In the present study, we have identified NEP to be a crucial player in the development of obesity. NEP-deficient mice start to become obese under a normocaloric diet in an age of 6–7 months and thus are an ideal model for the typical human late-onset obesity. Therefore, the described obesity model is an ideal tool for research on development, molecular mechanisms, diagnosis, and therapy of the pandemic obesity. Public Library of Science 2010-09-16 /pmc/articles/PMC2940827/ /pubmed/20862277 http://dx.doi.org/10.1371/journal.pone.0012793 Text en Becker 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
Becker, Matthias
Siems, Wolf-Eberhard
Kluge, Reinhart
Gembardt, Florian
Schultheiss, Heinz-Peter
Schirner, Michael
Walther, Thomas
New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity
title New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity
title_full New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity
title_fullStr New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity
title_full_unstemmed New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity
title_short New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity
title_sort new function for an old enzyme: nep deficient mice develop late-onset obesity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940827/
https://www.ncbi.nlm.nih.gov/pubmed/20862277
http://dx.doi.org/10.1371/journal.pone.0012793
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