Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure.
Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure.
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DOI：
10.1016/j.cmet.2013.03.005
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发表时间：
2013-04-02
期刊：
影响因子：
29
通讯作者：
Jiang ZY
中科院分区：
文献类型：
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作者：
Mansuy-Aubert V;Zhou QL;Xie X;Gong Z;Huang JY;Khan AR;Aubert G;Candelaria K;Thomas S;Shin DJ;Booth S;Baig SM;Bilal A;Hwang D;Zhang H;Lovell-Badge R;Smith SR;Awan FR;Jiang ZY
肥胖及相关并发症发生的分子机制尚不清楚。在这里，我们报告肥胖小鼠和人类受试者的中性粒细胞弹性酶（NE）活性增加，NE抑制剂α - 1抗胰蛋白酶（A1AT, SerpinA1）的血清水平降低。NE null （Ela2−/−）小鼠和A1AT转基因小鼠对高脂肪饮食（HFD）诱导的体重增加、胰岛素抵抗、炎症和脂肪肝具有抗性。NE抑制剂GW311616A逆转hfd喂养小鼠的胰岛素抵抗和体重增加。与野生型小鼠相比，Ela2−/−小鼠增加了循环高分子量（HMW）脂联素水平、肝脏和棕色脂肪组织（BAT）中amp活化蛋白激酶（AMPK）磷酸化和脂肪酸氧化（FAO），以及BAT中解偶联蛋白（UCP1）水平。这些数据表明，A1AT-NE系统调节AMPK信号、FAO和能量消耗。A1AT和NE之间的失衡导致肥胖及相关炎症、胰岛素抵抗和肝脏脂肪变性。
The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor, α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2−/−) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced bodyweight gain, insulin resistance, inflammation and fatty liver. NE inhibitor GW311616A reversed insulin resistance and bodyweight gain in HFD-fed mice. Compared with wild-type mice, Ela2−/− mice augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK) and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT), and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance and liver steatosis.
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DOI：
10.1038/nri2921
发表时间：
2011-02
期刊：
Nature reviews. Immunology
影响因子：
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影响因子：
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作者：
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影响因子：
82.9
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