Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation
Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation
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DOI：
10.2337/db06-0911
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发表时间：
2007-04-01
期刊：
影响因子：
7.7
通讯作者：
Shimomura, Iichiro
中科院分区：
文献类型：
--
作者：
Hosogai, Naomi;Fukuhara, Atsunori;Shimomura, Iichiro
肥胖与多种代谢紊乱有关，如胰岛素抵抗和动脉粥样硬化。脂肪源性分泌因子（脂肪细胞因子）的生产失调是肥胖相关代谢紊乱的部分原因。然而，肥胖本身对脂肪细胞因子失调的机制作用尚未完全阐明。在这里，我们表明，肥胖小鼠的脂肪组织是缺氧和局部脂肪组织缺氧失调的脂肪细胞因子的生产。通过外源性标记物哌莫硝唑和内源性标记物乳酸浓度升高证实组织缺氧。此外，在肥胖小鼠的脂肪组织中证实了局部组织灌注不足（通过有色微球测量）。肥胖小鼠脂肪组织中脂联素mRNA表达降低，内质网应激介导的C/EBP同源蛋白（CHOP）mRNA表达显著增加。在3 T3-L1脂肪细胞中，缺氧使脂肪细胞因子如脂联素和纤溶酶原激活物抑制剂1型的表达失调，并增加了ER应激标记基因CHOP和GRP 78（葡萄糖调节蛋白，78 kD）的mRNA。CHOP的表达减弱了脂联素启动子的活性，CHOP的RNA干扰部分逆转了缺氧诱导的脂肪细胞脂联素mRNA表达的抑制。缺氧也增加脂联素mRNA的不稳定性。我们的研究结果表明，低灌注和缺氧的脂肪组织的基础失调生产的脂肪细胞因子和代谢综合征的肥胖。
Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress-mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of adipocytokines and metabolic syndrome in obesity.