Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans
Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans
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DOI：
10.1172/jci37048
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发表时间：
2009-03-01
影响因子：
15.9
通讯作者：
Neufer, P. Darrell
中科院分区：
文献类型：
--
作者：
Anderson, Ethan J.;Lustig, Mary E.;Neufer, P. Darrell
高膳食脂肪摄入导致骨骼肌胰岛素抵抗，这是2型糖尿病和心血管疾病的主要危险因素。线粒体功能障碍和氧化应激已被牵连在疾病的过程中，但潜在的机制仍然是未知的。在这里，我们表明，在啮齿动物和人类的骨骼肌中，高脂肪饮食增加了线粒体的H2O2释放电位，将细胞的氧化还原环境转变为更氧化的状态，并在线粒体呼吸功能没有任何变化的情况下降低了氧化还原缓冲能力。此外，我们表明，衰减线粒体H2O2的排放，无论是通过治疗大鼠的神经靶向抗氧化剂或基因工程过氧化氢酶在小鼠肌肉线粒体的过度表达，完全保留胰岛素敏感性，尽管高脂肪饮食。这些发现表明，线粒体生物能量学的背景下，胰岛素抵抗的病因。H2O2的释放既是能量平衡的衡量标准，也是细胞氧化还原环境的调节剂，将细胞内代谢平衡与胰岛素敏感性的控制联系起来。
High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H2O2-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H2O2 emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial. H2O2 emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.