Lauhio Anneli, Färkkilä Esa, Pietiläinen Kirsi H, Åström Pirjo, Winkelmann Alina, Tervahartiala Taina, Pirilä Emma, Rissanen Aila, Kaprio Jaakko, Sorsa Timo A, Salo Tuula
Department of Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland.
Clinicum, University of Helsinki, Helsinki, Finland.
Eur J Clin Invest. 2016 Sep;46(9):757-65. doi: 10.1111/eci.12649.
Obesity has been recognized as a state of subclinical inflammation resulting in a loss of insulin receptors and decreased insulin sensitivity. We here studied in vivo the role of circulating matrix metalloproteinase-8 (MMP-8) among young healthy twin adults. Also, in vitro analysis of the cleavage of human insulin receptor (INSR) by MMP-8 was investigated as well its inhibition by doxycycline and other MMP-8 inhibitor, Ilomastat/GM6001, which are broad-spectrum MMP inhibitors.
We analysed serum MMP-8 levels by a time-resolved immunofluorometric assay in obese (n = 34), overweight (n = 76) and normal weight (n = 130) twin individuals. The effect of MMP-8 on INSR and the effects of synthetic MMP-8 inhibitors, doxycycline and Ilomastat/GM6001, were studied by SDS-PAGE.
We found that in obese individuals relative to normal weight individuals, the serum MMP-8 levels and MMP-8/TIMP-1 ratio were significantly increased (P = 0·0031 and P = 0·031, respectively). Among normal weight and obese individuals, also smoking significantly increases serum MMP-8 and MMP-8/TIMP-1 ratio. In vitro, we found that INSR was degraded by MMP-8 and this was inhibited by doxycycline and Ilomastat/GM6001.
Obesity associated with elevated circulating MMP-8 found among young adults may contribute to progression of insulin resistance by cleaving INSR. This INSR cleavage by MMP-8 can be inhibited by synthetic MMP-8 inhibitors such as doxycycline. In addition to obesity, also smoking independently explained increased MMP-8 levels. Our results suggest that MMP-8 is an essential mediator in systemic subclinical inflammatory response in obesity, and a potential drug target.
肥胖已被认为是一种亚临床炎症状态，会导致胰岛素受体丧失和胰岛素敏感性降低。我们在此研究了年轻健康双胞胎成年人中循环基质金属蛋白酶-8（MMP-8）的体内作用。此外，还研究了MMP-8对人胰岛素受体（INSR）的体外切割作用，以及强力霉素和其他MMP-8抑制剂伊洛马司他/GM6001（广谱MMP抑制剂）对其的抑制作用。
我们采用时间分辨免疫荧光分析法分析了肥胖（n = 34）、超重（n = 76）和正常体重（n = 130）双胞胎个体的血清MMP-8水平。通过SDS-PAGE研究了MMP-8对INSR的影响以及合成MMP-8抑制剂强力霉素和伊洛马司他/GM6001的作用。
我们发现，与正常体重个体相比，肥胖个体的血清MMP-8水平和MMP-8/TIMP-1比值显著升高（分别为P = 0·0031和P = 0·031）。在正常体重和肥胖个体中，吸烟也会显著增加血清MMP-8和MMP-8/TIMP-1比值。在体外，我们发现INSR被MMP-8降解，而强力霉素和伊洛马司他/GM6001可抑制这种降解。
在年轻人中发现的与循环MMP-8升高相关的肥胖可能通过切割INSR导致胰岛素抵抗的进展。MMP-8对INSR的这种切割作用可被强力霉素等合成MMP-8抑制剂抑制。除肥胖外，吸烟也独立解释了MMP-8水平的升高。我们的结果表明，MMP-8是肥胖全身性亚临床炎症反应中的重要介质，也是一个潜在的药物靶点。
