Matsuzawa-Nagata Naoto, Takamura Toshinari, Ando Hitoshi, Nakamura Seiji, Kurita Seiichiro, Misu Hirofumi, Ota Tsuguhito, Yokoyama Masayoshi, Honda Masao, Miyamoto Ken-ichi, Kaneko Shuichi
Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.
Metabolism. 2008 Aug;57(8):1071-7. doi: 10.1016/j.metabol.2008.03.010.
Insulin resistance is a key pathophysiological feature of metabolic syndrome. However, the initial events triggering the development of insulin resistance and its causal relations with dysregulation of glucose and fatty acids metabolism remain unclear. We investigated biological pathways that have the potential to induce insulin resistance in mice fed a high-fat diet (HFD). We demonstrate that the pathways for reactive oxygen species (ROS) production and oxidative stress are coordinately up-regulated in both the liver and adipose tissue of mice fed an HFD before the onset of insulin resistance through discrete mechanism. In the liver, an HFD up-regulated genes involved in sterol regulatory element binding protein 1c-related fatty acid synthesis and peroxisome proliferator-activated receptor alpha-related fatty acid oxidation. In the adipose tissue, however, the HFD down-regulated genes involved in fatty acid synthesis and up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Furthermore, increased ROS production preceded the elevation of tumor necrosis factor-alpha and free fatty acids in the plasma and liver. The ROS may be an initial key event triggering HFD-induced insulin resistance.
胰岛素抵抗是代谢综合征的关键病理生理特征。然而，引发胰岛素抵抗发展的初始事件及其与葡萄糖和脂肪酸代谢失调的因果关系仍不清楚。我们研究了在高脂饮食（HFD）喂养的小鼠中可能诱导胰岛素抵抗的生物学途径。我们证明，在胰岛素抵抗发生之前，通过离散机制，高脂饮食喂养的小鼠肝脏和脂肪组织中活性氧（ROS）产生和氧化应激途径均协同上调。在肝脏中，高脂饮食上调了与固醇调节元件结合蛋白1c相关的脂肪酸合成和过氧化物酶体增殖物激活受体α相关的脂肪酸氧化相关基因。然而，在脂肪组织中，高脂饮食下调了脂肪酸合成相关基因，并上调了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶复合物。此外，血浆和肝脏中ROS产生增加先于肿瘤坏死因子-α和游离脂肪酸升高。ROS可能是引发高脂饮食诱导的胰岛素抵抗的初始关键事件。
