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首页> 外文期刊>Molecular and Cellular Biology >Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose Tissue
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Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose Tissue

机译：缺氧诱导因子1α诱导白色脂肪组织的纤维化和胰岛素抵抗

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Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1α (HIF1α) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1α, we determined that HIF1α fails to induce the expected proangiogenic response. In contrast, we observed that HIF1α initiates adipose tissue fibrosis, with an associated increase in local inflammation. “Trichrome- and picrosirius red-positive streaks,” enriched in fibrillar collagens, are a hallmark of adipose tissue suffering from the early stages of hypoxia-induced fibrosis. Lysyl oxidase (LOX) is a transcriptional target of HIF1α and acts by cross-linking collagen I and III to form the fibrillar collagen fibers. Inhibition of LOX activity by β-aminoproprionitrile treatment results in a significant improvement in several metabolic parameters and further reduces local adipose tissue inflammation. Collectively, our observations are consistent with a model in which adipose tissue hypoxia serves as an early upstream initiator for adipose tissue dysfunction by inducing a local state of fibrosis.
机译：热量摄入过多时，脂肪组织可能会迅速膨胀。就像迅速扩大的肿瘤块一样，肥胖的脂肪组织由于脉管系统无法跟上组织生长的速度而变得缺氧。因此，在肥胖的早期阶段，低氧条件会导致缺氧诱导因子1α（HIF1α）表达水平增加。使用过表达HIF1α的组成型活性形式的转基因模型，我们确定HIF1α无法诱导预期的促血管生成反应。相反，我们观察到HIF1α启动脂肪组织纤维化，并伴有局部炎症的增加。富含纤维状胶原的“三色和picrosirius红阳性条纹”是患有缺氧性纤维化早期阶段的脂肪组织的标志。赖氨酰氧化酶（LOX）是HIF1α的转录靶标，通过交联I型和III型胶原形成原纤维胶原纤维而发挥作用。 β-氨基丙腈处理抑制LOX活性可显着改善几个代谢参数，并进一步减轻局部脂肪组织炎症。总的来说，我们的观察结果与一个模型一致，在该模型中，脂肪组织缺氧通过诱导局部纤维化状态而成为脂肪组织功能障碍的早期上游引发剂。

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