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The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice

Dobney Hypertension Centre, School of Medicine and Pharmacology, University of Western Australia, Crawley WA 6009, Australia
Research Centre, Royal Perth Hospital, Perth WA 6000, Australia
Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Department of Surgery, National Defense Medical College, Saitama 359-8513, Japan
Department of Cardiology and Department of Nephrology, Royal Perth Hospital, Perth WA 6000, Australia
Author to whom correspondence should be addressed.
Academic Editor: Masatoshi Maki
Int. J. Mol. Sci. 2017, 18(4), 884;
Received: 17 February 2017 / Revised: 6 April 2017 / Accepted: 18 April 2017 / Published: 21 April 2017
(This article belongs to the Special Issue Metalloproteins 2017)
PDF [2216 KB, uploaded 21 April 2017]


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. View Full-Text
Keywords: ADAM28; type 2 diabetes (T2D); obesity; metabolic syndrome; metalloproteinases ADAM28; type 2 diabetes (T2D); obesity; metabolic syndrome; metalloproteinases

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Herat, L.; Rudnicka, C.; Okada, Y.; Mochizuki, S.; Schlaich, M.; Matthews, V. The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice. Int. J. Mol. Sci. 2017, 18, 884.

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