Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

The metalloproteinase adam28 promotes metabolic dysfunction in humans and mice (#171)

Lakshini Herat 1 , Caroline Rudnicka 2 , Yasunori Okada 3 , Joanne Curran 4 , Matthew Johnson 4 , Eric Moses 1 , Harald Goring 4 , Satsuki Mochizuki 5 , John Blangero 4 , Markus Schlaich 1 2 , Vance Matthews 1
  1. University of Western Australia, Perth, WA, Australia
  2. Royal Perth Hospital, Perth, WA, Australia
  3. Juntendo University, Tokyo, Japan
  4. University of Texas Rio Grande Valley, Brownsville, Texas, USA
  5. National Defense Medical College, Saitama, Japan

Background:

Obesity and diabetes are major causes of morbidity and mortality globally. Metalloproteinases which cleave pro-inflammatory mediators from the cell surface have previously been implicated in the pathogenesis of high fat diet-induced obesity.

Aim(s):

Firstly, we aimed to ascertain whether the metalloproteinase ADAM28 correlates with parameters of the metabolic syndrome in humans and mice. Secondly, we endeavoured to determine the mechanisms by which ADAM28 may contribute to metabolic dysfunction. Thirdly, we assessed the effects of limiting ADAM28 activity on parameters of the metabolic syndrome in mice.

Method(s):

To identify novel metalloproteinases associated with the metabolic syndrome, micro-array studies were conducted in a well characterised human cohort. In vitro studies were performed to ascertain novel substrates of ADAM28. In addition, ADAM28 was knocked down in mice fed a high fat diet and metabolic parameters were assessed. Finally, ADAM28 knock-out mice were metabolically phenotyped.

Result(s):

We found that ADAM28 expression levels in lymphocytes isolated from a large human cohort strongly correlated with parameters of the metabolic syndrome. In in vitro studies, human ADAM28 promoted TNF-alpha shedding. This was significantly reduced when ADAM28 was inhibited by siRNA knock-down. In murine investigations, ADAM28 mRNA and protein expression was markedly increased in the livers of mice with the metabolic syndrome. Downregulation of ADAM28 with siRNA technology resulted in a lack of weight gain, promoted insulin sensitivity and glucose tolerance and decreased liver TNF-alpha levels in our diet-induced obesity mouse model. Additionally, ADAM28 knock-down improved kidney function and reduced liver injury. Similar metabolic benefits were also observed in ADAM28 knock-out mice.

Conclusions:

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.

  1. Jowett et al. 2012. ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-alpha. Immunology and Cell Biology 90: 966-73.
  2. Herat et al. 2017. The metalloproteinase ADAM28 promotes metabolic dysfunction in mice. Int. J. Mol. Sci. 18(4): 884 (doi:10.3390/ijms18040884).