Weerasekera Lakshini, Rudnicka Caroline, Sang Qing-Xiang, Curran Joanne E, Johnson Matthew P, Moses Eric K, Göring Harald H H, Blangero John, Hricova Jana, Schlaich Markus, Matthews Vance B
School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
Royal Perth Hospital, Perth, Australia.
Mediators Inflamm. 2017;2017:7281986. doi: 10.1155/2017/7281986. Epub 2017 Feb 7.
Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF- levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF- levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.
肥胖是西方世界最普遍的代谢性疾病之一，与胰岛素抵抗直接相关，而胰岛素抵抗最终可能会发展为2型糖尿病（T2D）。我们试图确定人类金属蛋白酶A解聚素和金属蛋白酶19（ADAM19）是否与人类和小鼠代谢综合征的参数相关。为了确定ADAM19在代谢综合征中的潜在新作用，我们首先对一个特征明确的人类队列的外周血单核细胞进行了微阵列研究。其次，我们使用体内饮食诱导肥胖小鼠模型检查了ADAM19在肝脏和性腺白色脂肪组织中的表达。最后，我们研究了中和ADAM19对饮食诱导的体重增加、体内胰岛素抵抗和肝脏肿瘤坏死因子水平的影响。值得注意的是，我们发现，在人类中，ADAM19与代谢综合征的参数密切相关，尤其是体重指数（BMI）、相对脂肪含量、稳态模型评估的胰岛素抵抗指数（HOMA-IR）和甘油三酯。此外，我们发现肥胖和T2D小鼠的肝脏和性腺白色脂肪组织中ADAM19的表达明显增加。令人兴奋的是，我们在饮食诱导肥胖小鼠模型中证明，中和ADAM19疗法可导致体重减轻、改善胰岛素敏感性并降低肝脏肿瘤坏死因子水平。我们的新数据表明，ADAM19具有促肥胖作用并增强胰岛素抵抗。因此，中和ADAM19可能是治疗肥胖和T2D的一种潜在治疗方法。
