Association of MMP-8 with obesity, smoking and insulin resistance

作者：Lauhio Anneli^*; Farkkila Esa; Pietilainen Kirsi H; Astrom Pirjo; Winkelmann Alina; Tervahartiala Taina; Pirila Emma; Rissanen Aila; Kaprio Jaakko; Sorsa Timo A; Salo Tuula

来源：European Journal of Clinical Investigation, 2016, 46(9): 757-765.

DOI：10.1111/eci.12649

• Insulin resistance
• MMP-8
• MMP-8 inhibitor
• obesity
• smoking
• therapy target

BackgroundObesity has been recognized as a state of subclinical inflammation resulting in a loss of insulin receptors and decreased insulin sensitivity. We here studied invivo the role of circulating matrix metalloproteinase-8 (MMP-8) among young healthy twin adults. Also, invitro 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.
Materials and methodsWe 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.
ResultsWe 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<bold></bold>0031 and P=0<bold></bold>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.
ConclusionsObesity 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.

• 出版日期2016-9