School of Korean Medicine, Pusan National University, 30 Beom-eo ri, Mulguem-eup, Yangsan-si, Gyeongnam, South Korea.
Biochem Biophys Res Commun. 2013 Feb 15;431(3):421-7. doi: 10.1016/j.bbrc.2012.12.154. Epub 2013 Jan 16.
Obesity-associated adipose tissue hypoxia plays a pivotal role in insulin resistance via impaired adipocyte dysfunction including mitochondria dysfunction. In this study, we investigated the involvement of hypoxia-inducible ATF3 in adipocyte hypoxia-mediated mitochondrial dysfunction. While HIF-1α and ATF3 were increased in white adipose tissue of high fat diet (HFD) obese mice compared with control lean mice, mitochondria-related genes were significantly reduced. Treatment with hypoxia mimetics CoCl(2) or incubation with 2% O(2) impaired mitochondria function as demonstrated by decreases in ATP production, NADH dehydrogenase activity, mitochondrial membrane potential, and reduced expression of mitochondria-related genes including NRF-1, PGC-1α, COX1 and SOD in 3T3-L1 adipocyte cells. Furthermore, overexpression of ATF3 in 3T3-L1 cells also decreased mitochondria function as well as expression of mitochondria-related genes. ATF3 knockdown in 3T3-L1 cells partly prevented the hypoxia-mediated decrease in mitochondria function and expression of mitochondria-related genes. The mitochondria-related genes were decreased in white adipose tissue of ATF3-overexpressing mice compared with wild-type mice. These results suggest that ATF3 may play a role in adipocyte hypoxia-mediated mitochondrial dysfunction in obesity.
肥胖相关的脂肪组织缺氧通过损害脂肪细胞功能（包括线粒体功能）在胰岛素抵抗中发挥关键作用。在这项研究中，我们研究了缺氧诱导因子 ATF3 在脂肪细胞缺氧介导的线粒体功能障碍中的作用。与对照瘦小鼠相比，高脂肪饮食（HFD）肥胖小鼠的白色脂肪组织中 HIF-1α 和 ATF3 增加，而与线粒体相关的基因显著减少。用缺氧模拟物 CoCl2 处理或在 2% O2 中孵育会损害线粒体功能，表现为三磷酸腺苷（ATP）产生减少、烟酰胺腺嘌呤二核苷酸脱氢酶活性降低、线粒体膜电位降低，以及 3T3-L1 脂肪细胞中线粒体相关基因的表达减少，包括 NRF-1、PGC-1α、COX1 和 SOD。此外，在 3T3-L1 细胞中转染 ATF3 过表达也会降低线粒体功能以及线粒体相关基因的表达。在 3T3-L1 细胞中转染 ATF3 敲低部分预防了缺氧介导的线粒体功能和线粒体相关基因表达的降低。与野生型小鼠相比，ATF3 过表达小鼠的白色脂肪组织中线粒体相关基因减少。这些结果表明，ATF3 可能在肥胖相关的脂肪细胞缺氧介导的线粒体功能障碍中发挥作用。
