Discipline of Nutrition, School of Medical Sciences, University of Auckland, Auckland, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Am J Physiol Endocrinol Metab. 2021 Oct 1;321(4):E560-E570. doi: 10.1152/ajpendo.00181.2021. Epub 2021 Sep 6.
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 intraperitoneal injections three times weekly of either Prolastin (human A1AT; 2 mg) or vehicle (PBS) for 10 wk. 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 phosphorylation, 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 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. Neutrophils accumulate in peripheral tissues during obesity and are critical coordinators of tissue inflammatory responses. Here, we provide evidence that inhibition of the primary neutrophil protease, neutrophil elastase, with α1-antitrypsin A (A1AT) can improve insulin sensitivity and glucose homeostasis of mice fed a high-fat diet. This was attributed to improved insulin-induced IRS-1 phosphorylation in white adipose tissue and provides further support for a role of neutrophils in mediating diet-induced peripheral tissue insulin resistance.
中性粒细胞在肥胖时积聚在胰岛素敏感组织中，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)，其被内源性 α1-抗胰蛋白酶 A (A1AT) 抑制。我们研究了外源性（A1AT）治疗对饮食引起的代谢功能障碍的影响。给予雄性 C57Bl/6j 小鼠普通饮食或高脂肪饮食（HFD），每周腹腔注射三次 Prolastin（人 A1AT；2mg）或载体（PBS），共 10 周。Prolastin 治疗不影响正常饮食喂养的小鼠的血浆 NE 浓度、体重、葡萄糖耐量或胰岛素敏感性。相比之下，Prolastin 治疗可减轻 HFD 诱导的血浆和白色脂肪组织 (WAT) NE 增加，而不影响循环中性粒细胞水平或体重增加。给予 HFD 的 Prolastin 治疗的小鼠胰岛素敏感性改善，如胰岛素耐量试验所示，这与更高的胰岛素依赖性 IRS-1（胰岛素受体底物）和 Akt 磷酸化以及 WAT 中炎症标志物减少有关，但与肝脏或肌肉无关。在 3T3-L1 脂肪细胞中，Prolastin 逆转了重组 NE 诱导的胰岛素刺激的葡萄糖摄取和 IRS-1 磷酸化受损。此外，PDGF 介导的 p-Akt 激活和葡萄糖摄取（不依赖于 IRS-1）不受重组 NE 处理的影响。总之，我们的研究结果表明，代谢超负荷期间 WAT 中的 NE 浸润通过损害胰岛素诱导的 IRS-1 信号传导导致胰岛素抵抗。中性粒细胞在肥胖期间积聚在周围组织中，是组织炎症反应的关键协调者。在这里，我们提供的证据表明，用 α1-抗胰蛋白酶 A (A1AT) 抑制主要中性粒细胞蛋白酶，中性粒细胞弹性蛋白酶，可改善高脂肪饮食喂养的小鼠的胰岛素敏感性和葡萄糖稳态。这归因于白色脂肪组织中胰岛素诱导的 IRS-1 磷酸化改善，并为中性粒细胞在介导饮食引起的外周组织胰岛素抵抗方面的作用提供了进一步的支持。
