Neutrophils accumulate in insulin sensitive tissues during obesity and may play a role in impairing insulin sensitivity. The major serine protease expressed by neutrophils is neutrophil elastase (NE), which is inhibited endogenously by α1-antitrypsin A (A1AT). We investigated the effect of exogenous (A1AT) treatment on diet induced metabolic dysfunction. Male C57Bl/6j mice fed a chow or a high fat diet (HFD) were randomized to receive 3x weekly i.p injections of either Prolastin (human A1AT; 2mg) or vehicle (PBS) for 10 weeks. Prolastin treatment did not affect plasma NE concentration, body weight, glucose tolerance or insulin sensitivity in chow fed mice. In contrast, Prolastin treatment attenuated HFD induced increases in plasma and white adipose tissue (WAT) NE without affecting circulatory neutrophil levels or increases in body weight. Prolastin-treated mice fed a HFD had improved insulin sensitivity, as assessed by insulin tolerance test, and this was associated with higher insulin-dependent IRS-1 (insulin receptor substrate) and Akt^Ser473phosphorylation, and reduced inflammation markers in WAT but not liver or muscle. In 3T3-L1 adipocytes, Prolastin reversed recombinant NE-induced impairment of insulin-stimulated glucose uptake and IRS-1 phosphorylation. Furthermore, PDGF mediated p-Akt^Ser473 activation and glucose uptake (which is independent of IRS-1) was not affected by recombinant NE treatment. Collectively, our findings suggest that NE infiltration of WAT during metabolic overload contributes to insulin-resistance by impairing insulin-induced IRS-1 signaling.

中文翻译：

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α1-抗胰蛋白酶 A 治疗可减弱中性粒细胞弹性蛋白酶的积累并增强高脂肪饮食小鼠脂肪组织中的胰岛素敏感性。

中性粒细胞在肥胖期间会在胰岛素敏感组织中积聚，并可能在损害胰岛素敏感性方面发挥作用。中性粒细胞表达的主要丝氨酸蛋白酶是中性粒细胞弹性蛋白酶 (NE)，它被 α1-抗胰蛋白酶 A (A1AT) 内源性抑制。我们研究了外源性 (A1AT) 治疗对饮食诱导的代谢功能障碍的影响。喂食食物或高脂肪饮食 (HFD) 的雄性 C57Bl/6j 小鼠随机接受每周 3 次 ip 注射 Prolastin（人 A1AT；2mg）或载体 (PBS) 10 周。前列腺素处理不影响饲料喂养小鼠的血浆 NE 浓度、体重、葡萄糖耐量或胰岛素敏感性。相比之下，Prolastin 治疗减弱了 HFD 诱导的血浆和白色脂肪组织 (WAT) NE 的增加，而不影响循环中性粒细胞水平或体重增加。^Ser473磷酸化，并减少 WAT 中的炎症标志物，但不是肝脏或肌肉。在 3T3-L1 脂肪细胞中，Prolastin 逆转了重组 NE 诱导的胰岛素刺激葡萄糖摄取和 IRS-1 磷酸化的损伤。此外，PDGF 介导的 p-Akt ^Ser473活化和葡萄糖摄取（独立于 IRS-1）不受重组 NE 治疗的影响。总的来说，我们的研究结果表明，代谢超负荷期间 WAT 的 NE 浸润通过削弱胰岛素诱导的 IRS-1 信号传导而导致胰岛素抵抗。