Lee Jung-Ting, Pamir Nathalie, Liu Ning-Chun, Kirk Elizabeth A, Averill Michelle M, Becker Lev, Larson Ilona, Hagman Derek K, Foster-Schubert Karen E, van Yserloo Brian, Bornfeldt Karin E, LeBoeuf Renee C, Kratz Mario, Heinecke Jay W
Departments of Medicine (J.-T.L., N.P., N.-C.L., M.M.A., L.B., K.E.F.-S., B.V.Y., K.E.B., R.C.L., M.K., J.W.H.), Pathology (K.E.B.), and Epidemiology (E.A.K., M.K.), University of Washington, Seattle, Washington 98105; and Fred Hutchinson Cancer Research Center (D.K.H., M.K.), Public Health Sciences, Seattle, Washington 98103.
Endocrinology. 2014 Sep;155(9):3409-20. doi: 10.1210/en.2014-1037. Epub 2014 Jun 10.
Macrophage metalloelastase, a matrix metallopeptidase (MMP12) predominantly expressed by mature tissue macrophages, is implicated in pathological processes. However, physiological functions for MMP12 have not been described. Because mRNA levels for the enzyme increase markedly in adipose tissue of obese mice, we investigated the role of MMP12 in adipose tissue expansion and insulin resistance. In humans, MMP12 expression correlated positively and significantly with insulin resistance, TNF-α expression, and the number of CD14(+)CD206(+) macrophages in adipose tissue. MMP12 was the most abundant matrix metallopeptidase detected by proteomic analysis of conditioned medium of M2 macrophages and dendritic cells. In contrast, it was detected only at low levels in bone marrow derived macrophages and M1 macrophages. When mice received a high-fat diet, adipose tissue mass increased and CD11b(+)F4/80(+)CD11c(-) macrophages accumulated to a greater extent in MMP12-deficient (Mmp12(-/-)) mice than in wild-type mice (Mmp12(+/+)). Despite being markedly more obese, fat-fed Mmp12(-/-) mice were more insulin sensitive than fat-fed Mmp12(+/+) mice. Expression of inducible nitric oxide synthase (Nos2) by Mmp12(-/-) macrophages was significantly impaired both in vivo and in vitro, suggesting that MMP12 might mediate nitric oxide production during inflammation. We propose that MMP12 acts as a double-edged sword by promoting insulin resistance while combatting adipose tissue expansion.
巨噬细胞金属弹性蛋白酶是一种主要由成熟组织巨噬细胞表达的基质金属肽酶（MMP12），与病理过程有关。然而，MMP12的生理功能尚未见报道。由于该酶的mRNA水平在肥胖小鼠的脂肪组织中显著增加，我们研究了MMP12在脂肪组织扩张和胰岛素抵抗中的作用。在人类中，MMP12的表达与胰岛素抵抗、TNF-α表达以及脂肪组织中CD14(+)CD206(+)巨噬细胞的数量呈显著正相关。通过对M2巨噬细胞和树突状细胞条件培养基的蛋白质组分析发现，MMP12是检测到的最丰富的基质金属肽酶。相比之下，在骨髓来源的巨噬细胞和M1巨噬细胞中仅检测到低水平的MMP12。当小鼠接受高脂饮食时，与野生型小鼠（Mmp12(+/+)）相比，MMP12缺陷型（Mmp12(-/-)）小鼠的脂肪组织质量增加，CD11b(+)F4/80(+)CD11c(-)巨噬细胞积累的程度更大。尽管Mmp12(-/-)小鼠明显更肥胖，但高脂喂养的Mmp12(-/-)小鼠比高脂喂养的Mmp12(+/+)小鼠对胰岛素更敏感。Mmp12(-/-)巨噬细胞中诱导型一氧化氮合酶（Nos2）的表达在体内和体外均显著受损，这表明MMP12可能在炎症过程中介导一氧化氮的产生。我们认为，MMP12通过促进胰岛素抵抗同时对抗脂肪组织扩张而起到双刃剑的作用。
