Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain
Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain
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DOI：
10.1172/jci.insight.130681
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发表时间：
2019-09-19
期刊：
影响因子：
8
通讯作者：
Nair, K. Sreekumaran
中科院分区：
文献类型：
--
作者：
Ruegsegger, Gregory N.;Vanderboom, Patrick M.;Nair, K. Sreekumaran
胰岛素抵抗与认知能力下降和痴呆的风险增加有关;然而，这种风险增加的基础机制仍有待完全确定。由于胰岛素抵抗损害线粒体氧化代谢并增加骨骼肌中的ROS，我们考虑了类似的事件是否发生在大脑中，大脑和肌肉一样富含胰岛素受体和线粒体。我们发现，高脂饮食诱导（HFD诱导）的小鼠脑胰岛素抵抗降低线粒体ATP的生产率和氧化酶的活动，在大脑区域丰富的胰岛素受体。HFD增加了ROS的排放，降低了抗氧化酶的活性，同时积累了氧化损伤的线粒体蛋白，增加了线粒体分裂。通过有氧运动和二甲双胍改善胰岛素敏感性可改善HFD诱导的异常。此外，胰岛素诱导的初级皮质神经元和星形胶质细胞ATP产生的增强被胰岛素受体拮抗剂S961抵消，表明胰岛素抵抗对脑线粒体的直接影响。此外，鼻内S961给药阻止了HFD期间运动诱导的ATP产生和ROS排放的改善，支持运动增强脑线粒体！通过改善胰岛素的作用。这些结果支持通过运动和二甲双胍的胰岛素增敏作用恢复胰岛素抵抗状态下的脑线粒体功能。
Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully defined. As insulin resistance impairs mitochondrial oxidative metabolism and increases ROS in skeletal muscle, we considered whether similar events occur in the brain, which - like muscle - is rich in insulin receptors and mitochondria. We show that high-fat diet-induced (HFD-induced) brain insulin resistance in mice decreased mitochondrial ATP production rate and oxidative enzyme activities in brain regions rich in insulin receptors. HFD increased ROS emission and reduced antioxidant enzyme activities, with the concurrent accumulation of oxidatively damaged mitochondrial proteins and increased mitochondrial fission. Improvement of insulin sensitivity by both aerobic exercise and metformin ameliorated HFD-induced abnormalities. Moreover, insulin-induced enhancement of ATP production in primary cortical neurons and astrocytes was counteracted by the insulin receptor antagonist S961, demonstrating a direct effect of insulin resistance on brain mitochondria. Further, intranasal S961 administration prevented exercise-induced improvements in ATP production and ROS emission during HFD, supporting that exercise enhances brain mitochondria! function by improving insulin action. These results support that insulin sensitizing by exercise and metformin restores brain mitochondrial function in insulin-resistant states.