TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents
TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents
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DOI：
10.1172/jci28570
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发表时间：
2006-10-01
影响因子：
15.9
通讯作者：
Nisoli, Enzo
中科院分区：
文献类型：
--
作者：
Valerio, Alessandra;Cardile, Annalisa;Nisoli, Enzo
肥胖与慢性低度炎症有关。因此，在代谢相关的部位，包括脂肪组织和肌肉，存在促炎细胞因子的异常产生，如肿瘤坏死因子-α。在这里，我们证明了eNOS在3种不同肥胖动物模型的白色和棕色脂肪组织以及比目鱼肌中的表达减少，并伴随着线粒体生物合成和功能的减少。肥胖小鼠的肿瘤坏死因子受体1的基因缺失恢复了脂肪和肌肉中eNOS的表达和线粒体的生物生成；这与体重增加比肥胖的野生型对照小鼠少有关。此外，在培养的小鼠白色和棕色脂肪细胞和肌肉卫星细胞中，肿瘤坏死因子-α下调eNOS的表达和线粒体的生物合成。NO供体DETA-NO和SNAP阻止了用肿瘤坏死因子-α观察到的线粒体生物发生的减少。我们的研究表明，肿瘤坏死因子-α通过下调eNOS的表达来损害肥胖啮齿动物不同组织中线粒体的生物发生和功能，提示了一种新的维持肥胖的病理生理过程。
Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-alpha. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-alpha downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-alpha.Ourfmdings demonstrate that TNF-a impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.