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The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice

Obesity and diabetes are major causes of morbidity and mortality globally. The current study builds upon our previous association studies highlighting that A Disintegrin And Metalloproteinase 28 (ADAM28) appears to be implicated in the pathogenesis of obesity and type 2 diabetes in humans. Our novel...

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Autores principales: Herat, Lakshini, Rudnicka, Caroline, Okada, Yasunori, Mochizuki, Satsuki, Schlaich, Markus, Matthews, Vance
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412464/
https://www.ncbi.nlm.nih.gov/pubmed/28430139
http://dx.doi.org/10.3390/ijms18040884
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author Herat, Lakshini
Rudnicka, Caroline
Okada, Yasunori
Mochizuki, Satsuki
Schlaich, Markus
Matthews, Vance
author_facet Herat, Lakshini
Rudnicka, Caroline
Okada, Yasunori
Mochizuki, Satsuki
Schlaich, Markus
Matthews, Vance
author_sort Herat, Lakshini
collection PubMed
description Obesity and diabetes are major causes of morbidity and mortality globally. The current study builds upon our previous association studies highlighting that A Disintegrin And Metalloproteinase 28 (ADAM28) appears to be implicated in the pathogenesis of obesity and type 2 diabetes in humans. Our novel study characterised the expression of ADAM28 in mice with the metabolic syndrome and used molecular inhibition approaches to investigate the functional role of ADAM28 in the pathogenesis of high fat diet-induced obesity. We identified that ADAM28 mRNA and protein expression was markedly increased in the livers of mice with the metabolic syndrome. In addition, noradrenaline, the major neurotransmitter of the sympathetic nervous system, results in elevated Adam28 mRNA expression in human monocytes. Downregulation of ADAM28 with siRNA technology resulted in a lack of weight gain, promotion of insulin sensitivity/glucose tolerance and decreased liver tumour necrosis factor-α (TNF-α) levels in our diet-induced obesity mouse model as well as reduced blood urea nitrogen, alkaline phosphatase and aspartate aminotransferase. In addition, we show that ADAM28 knock-out mice also displayed reduced body weight, elevated high density lipoprotein cholesterol levels, and reductions in blood urea nitrogen, alkaline phosphatase, and aspartate aminotransferase. The results of this study provide important insights into the pathogenic role of the metalloproteinase ADAM28 in the metabolic syndrome and suggests that downregulation of ADAM28 may be a potential therapeutic strategy in the metabolic syndrome.
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spelling pubmed-54124642017-05-05 The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice Herat, Lakshini Rudnicka, Caroline Okada, Yasunori Mochizuki, Satsuki Schlaich, Markus Matthews, Vance Int J Mol Sci Article Obesity and diabetes are major causes of morbidity and mortality globally. The current study builds upon our previous association studies highlighting that A Disintegrin And Metalloproteinase 28 (ADAM28) appears to be implicated in the pathogenesis of obesity and type 2 diabetes in humans. Our novel study characterised the expression of ADAM28 in mice with the metabolic syndrome and used molecular inhibition approaches to investigate the functional role of ADAM28 in the pathogenesis of high fat diet-induced obesity. We identified that ADAM28 mRNA and protein expression was markedly increased in the livers of mice with the metabolic syndrome. In addition, noradrenaline, the major neurotransmitter of the sympathetic nervous system, results in elevated Adam28 mRNA expression in human monocytes. Downregulation of ADAM28 with siRNA technology resulted in a lack of weight gain, promotion of insulin sensitivity/glucose tolerance and decreased liver tumour necrosis factor-α (TNF-α) levels in our diet-induced obesity mouse model as well as reduced blood urea nitrogen, alkaline phosphatase and aspartate aminotransferase. In addition, we show that ADAM28 knock-out mice also displayed reduced body weight, elevated high density lipoprotein cholesterol levels, and reductions in blood urea nitrogen, alkaline phosphatase, and aspartate aminotransferase. The results of this study provide important insights into the pathogenic role of the metalloproteinase ADAM28 in the metabolic syndrome and suggests that downregulation of ADAM28 may be a potential therapeutic strategy in the metabolic syndrome. MDPI 2017-04-21 /pmc/articles/PMC5412464/ /pubmed/28430139 http://dx.doi.org/10.3390/ijms18040884 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Herat, Lakshini
Rudnicka, Caroline
Okada, Yasunori
Mochizuki, Satsuki
Schlaich, Markus
Matthews, Vance
The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice
title The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice
title_full The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice
title_fullStr The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice
title_full_unstemmed The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice
title_short The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice
title_sort metalloproteinase adam28 promotes metabolic dysfunction in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412464/
https://www.ncbi.nlm.nih.gov/pubmed/28430139
http://dx.doi.org/10.3390/ijms18040884
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