脂肪细胞耗氧量增加会触发缺氧诱导因子-1α（HIF-1α），从而在肥胖状态下引发炎症和胰岛素抵抗。
Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity.
作者信息
Lee Yun Sok, Kim Jung-Whan, Osborne Olivia, Oh Da Young, Sasik Roman, Schenk Simon, Chen Ai, Chung Heekyung, Murphy Anne, Watkins Steven M, Quehenberger Oswald, Johnson Randall S, Olefsky Jerrold M
机构信息
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
出版信息
Cell. 2014 Jun 5;157(6):1339-1352. doi: 10.1016/j.cell.2014.05.012.
Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.
脂肪组织缺氧和炎症与肥胖诱导的胰岛素抵抗存在因果关系。在此，我们报告，在高脂饮食（HFD）喂养和肥胖过程的早期，脂肪细胞呼吸解偶联，导致氧消耗增加和相对的脂肪细胞缺氧状态。这些事件足以触发缺氧诱导因子-1α（HIF-1α）的诱导，引发肥胖特有的慢性脂肪组织炎症反应。在分子水平上，这些事件涉及饱和脂肪酸对腺嘌呤核苷酸转位酶2（ANT2，一种线粒体内膜蛋白）的刺激，从而导致呼吸解偶联状态。对ANT2或HIF-1α进行基因或药物抑制可预防或逆转这些病理生理事件，恢复胰岛素敏感性和葡萄糖耐量状态。这些结果揭示了肥胖诱导的炎症和胰岛素抵抗中的一系列连续事件。
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