Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
Adv Exp Med Biol. 2024;1460:329-356. doi: 10.1007/978-3-031-63657-8_11.
Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thereby, compared to lean subjects, obese individuals have almost half lower capillary density and more than half lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 alpha (HIF-1α) activity also requires phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR)-mediated signaling. Especially HIF-1α is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia contributes to several biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation, and insulin resistance (IR). Pathogenesis of obesity-related comorbidities is attributed to intermittent hypoxia (IH), which is mostly observed in visceral obesity. Proinflammatory phenotype of the adipose tissue is a crucial link between IH and the development of IR. Inhibition of adaptive unfolded protein response (UPR) in hypoxia increases β cell death. Moreover, deletion of HIF-1α worsens β cell function. Oxidative stress, as well as the release of proinflammatory cytokines/adipokines in obesity, is proportional to the severity of IH. Reactive oxygen species (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal; however, mitochondrial ROS production is required for hypoxic HIF-1α protein stabilization. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible for the dysregulated adipocytokines production in obesity. Hypoxia both inhibits adipocyte differentiation from preadipocytes and macrophage migration from the hypoxic adipose tissue. Upon reaching a hypertrophic threshold beyond the adipocyte fat loading capacity, excess extracellular matrix (ECM) components are deposited, causing fibrosis. HIF-1α initiates the whole pathological process of fibrosis and inflammation in the obese adipose tissue. In addition to stressed adipocytes, hypoxia contributes to immune cell migration and activation which further aggravates adipose tissue fibrosis. Therefore, targeting HIF-1α might be an efficient way to suppress hypoxia-induced pathological changes in the ECM. The fibrosis score of adipose tissue correlates negatively with the body mass index and metabolic parameters. Inducers of browning/beiging adipocytes and adipokines, as well as modulations of matrix remodeling enzyme inhibitors, and associated gene regulators, are potential pharmacological targets for treating obesity.
肥胖受试者的脂肪组织耗氧量较低，这与脂肪组织血流量较低有关。因此，与瘦受试者相比，肥胖个体的毛细血管密度低近一半，血管内皮生长因子 (VEGF) 高 1 倍以上。VEGF 表达以及缺氧诱导因子-1α (HIF-1α) 活性还需要磷脂酰肌醇 3-激酶 (PI3K) 和哺乳动物雷帕霉素靶蛋白 (mTOR) 介导的信号转导。特别是 HIF-1α 是缺氧诱导炎症反应的重要信号分子。缺氧有助于多种生物学功能，如血管生成、细胞增殖、凋亡、炎症和胰岛素抵抗 (IR)。肥胖相关合并症的发病机制归因于间歇性缺氧 (IH)，这种缺氧主要发生在内脏肥胖中。脂肪组织的促炎表型是 IH 与 IR 发展之间的关键环节。缺氧时适应性未折叠蛋白反应 (UPR) 的抑制会增加β细胞死亡。此外，HIF-1α 的缺失会使β细胞功能恶化。氧化应激以及肥胖中促炎细胞因子/脂肪因子的释放与 IH 的严重程度成正比。线粒体中活性氧 (ROS) 的产生负责传递缺氧信号；然而，ROS 的产生对于缺氧 HIF-1α 蛋白的稳定是必需的。脂肪组织氧供应的变化直接影响巨噬细胞极化，并负责肥胖中失调的脂肪细胞因子产生。缺氧既抑制前脂肪细胞向脂肪细胞的分化，也抑制巨噬细胞从缺氧脂肪组织中的迁移。当达到脂肪细胞脂肪负荷能力的肥大阈值时，过量的细胞外基质 (ECM) 成分会沉积，导致纤维化。HIF-1α 启动肥胖脂肪组织纤维化和炎症的整个病理过程。除了应激脂肪细胞外，缺氧还促进免疫细胞的迁移和激活，从而进一步加剧脂肪组织纤维化。因此，靶向 HIF-1α 可能是抑制 ECM 中缺氧诱导的病理变化的有效方法。脂肪组织的纤维化评分与体重指数和代谢参数呈负相关。诱导棕色/米色脂肪细胞和脂肪因子、调节基质重塑酶抑制剂以及相关基因调节剂，是治疗肥胖的潜在药理学靶点。
