Subauste Angela R, Burant Charles F
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E159-64. doi: 10.1152/ajpendo.00629.2006. Epub 2007 Mar 20.
Reactive oxygen species (ROS) production has recently been established as an essential contributor in the pathogenesis of obesity-associated insulin resistance. The FoxO1 pathway plays a role not only in nutrient sensing but also in regulating ROS production. We exposed adipocytes to free fatty acids (FFA) and demonstrated that FoxO1 protein levels decrease in a dose-dependent manner. The FoxO1 downregulation correlated with an increase in the production of ROS and a proinflammatory adipokine pattern characterized by a decrease in adiponectin and an increase in IL-6, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1 mRNA expression levels. Similarly, a decrease in FoxO1 protein levels was seen in adipocytes of db/db mice compared with controls. Treatment with the sirtuin agonist resveratrol, which translocates FoxO1 to the nucleus, increased FoxO1 protein levels in adipocytes exposed to FFA. This correlated with a decrease in the generation of ROS and a partial reversal of the proinflammatory adipokine pattern. Together these results indicate that the insulin-resistant adipocyte produced by the exposure to a high concentration of fatty acids is characterized by decreased levels of FoxO1. These data also suggest that modulation of the Sirt1/FoxO1 pathway is a potentially useful therapeutic target for the obesity-induced dysfunctional adipocyte.
活性氧（ROS）的产生最近已被确认为肥胖相关胰岛素抵抗发病机制中的一个重要因素。FoxO1途径不仅在营养感知中起作用，还在调节ROS产生中发挥作用。我们将脂肪细胞暴露于游离脂肪酸（FFA）中，结果表明FoxO1蛋白水平呈剂量依赖性降低。FoxO1的下调与ROS产生增加以及以脂联素减少和白细胞介素-6、纤溶酶原激活物抑制剂-1和单核细胞趋化蛋白-1 mRNA表达水平增加为特征的促炎脂肪因子模式相关。同样，与对照组相比，db/db小鼠的脂肪细胞中FoxO1蛋白水平也有所降低。用将FoxO1转运至细胞核的沉默调节蛋白激动剂白藜芦醇处理，可增加暴露于FFA的脂肪细胞中FoxO1蛋白水平。这与ROS生成减少以及促炎脂肪因子模式的部分逆转相关。这些结果共同表明，暴露于高浓度脂肪酸产生的胰岛素抵抗脂肪细胞的特征是FoxO1水平降低。这些数据还表明，调节Sirt1/FoxO1途径可能是肥胖诱导的功能失调脂肪细胞的一个有用治疗靶点。
