Adipose Tissue Hypoxia in Obesity and Its Impact on Preadipocytes and Macrophages: Hypoxia Hypothesis
Adipose Tissue Hypoxia in Obesity and Its Impact on Preadipocytes and Macrophages: Hypoxia Hypothesis
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DOI：
10.1007/978-3-319-48382-5_13
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发表时间：
2017-01-01
期刊：
影响因子：
--
通讯作者：
Engin, Atilla
中科院分区：
文献类型：
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作者：
Engin, Atilla
肥胖受试者表现出与较低脂肪组织血流量一致的较低脂肪组织耗氧量。因此，与瘦型受试者相比，肥胖受试者的毛细血管密度低44%，血管内皮生长因子（VEGF）低58%。VEGF表达与缺氧诱导转录因子-1（HIF-1）活性一起还需要磷脂酰肌醇3-激酶（PI 3 K）和雷帕霉素靶点（TOR）介导的信号传导。HIF-1 α是缺氧诱导炎症反应的重要信号分子。缺氧影响许多生物学功能，如血管生成、细胞增殖、凋亡、炎症和胰岛素抵抗。此外，线粒体处的活性氧自由基（ROS）产生负责缺氧信号的传播。实际上，缺氧HIF-1 α蛋白的稳定需要线粒体活性氧（mtROS）的产生，而不是氧气的消耗。与非肥胖成年人相比，肥胖者脂肪细胞线粒体氧化能力降低。在这方面，脂肪细胞的线粒体功能障碍与总体肥胖相关。此外，缺氧还抑制巨噬细胞从缺氧脂肪组织迁移。脂肪组织的氧利用率的改变直接影响巨噬细胞极化，并且是肥胖症中脂肪细胞因子产生失调的原因。缺氧还抑制前脂肪细胞向脂肪细胞分化。除了应激的脂肪细胞，缺氧有助于免疫细胞的迁移和激活，这进一步加剧了脂肪组织纤维化。纤维化是响应于肥胖症中的脂肪细胞肥大而启动的。
Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thus, compared with lean subjects, obese subjects have 44% lower capillary density and 58% lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 (HIF-1) activity also requires phosphatidylinositol 3-kinase (PI3K)- and target of rapamycin (TOR)-mediated signaling. HIF-1alpha is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia affects a number of biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation and insulin resistance. Additionally, reactive oxygen radical (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal. Actually mitochondrial ROS (mtROS) production, but not oxygen consumption is required for hypoxic HIF-1alpha protein stabilization. Adipocyte mitochondrial oxidative capacity is reduced in obese compared with non-obese adults. In this respect, mitochondrial dysfunction of adipocyte is associated with the overall adiposity. Furthermore, hypoxia also inhibits macrophage migration from the hypoxic adipose tissue. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible from dysregulated adipocytokines production in obesity. Hypoxia also inhibits adipocyte differentiation from preadipocytes. In addition to stressed adipocytes, hypoxia contributes to immune cell immigration and activation which further aggravates adipose tissue fibrosis. Fibrosis is initiated in response to adipocyte hypertrophy in obesity.