Filippi Beatrice M, Abraham Mona A, Silva Pamuditha N, Rasti Mozhgan, LaPierre Mary P, Bauer Paige V, Rocheleau Jonathan V, Lam Tony K T
Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada.
Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Cell Rep. 2017 Mar 7;18(10):2301-2309. doi: 10.1016/j.celrep.2017.02.035.
Mitochondria undergo dynamic changes to maintain function in eukaryotic cells. Insulin action in parallel regulates glucose homeostasis, but whether specific changes in mitochondrial dynamics alter insulin action and glucose homeostasis remains elusive. Here, we report that high-fat feeding in rodents incurred adaptive dynamic changes in mitochondria through an increase in mitochondrial fission in parallel to an activation of dynamin-related protein 1 (Drp1) in the dorsal vagal complex (DVC) of the brain. Direct inhibition of Drp1 negated high-fat-feeding-induced mitochondrial fission, endoplasmic reticulum (ER) stress, and insulin resistance in the DVC and subsequently restored hepatic glucose production regulation. Conversely, molecular activation of DVC Drp1 in healthy rodents was sufficient to induce DVC mitochondrial fission, ER stress, and insulin resistance. Together, these data illustrate that Drp1-dependent mitochondrial fission changes in the DVC regulate insulin action and suggest that targeting the Drp1-mitochondrial-dependent pathway in the brain may have therapeutic potential in insulin resistance.
线粒体发生动态变化以维持真核细胞的功能。胰岛素作用同时调节葡萄糖稳态，但线粒体动态的特定变化是否会改变胰岛素作用和葡萄糖稳态仍不清楚。在此，我们报告，啮齿动物高脂喂养会通过增加线粒体裂变，导致线粒体发生适应性动态变化，同时大脑背侧迷走神经复合体（DVC）中与发动蛋白相关蛋白1（Drp1）被激活。直接抑制Drp1可消除高脂喂养诱导的DVC线粒体裂变、内质网（ER）应激和胰岛素抵抗，并随后恢复肝脏葡萄糖生成调节。相反，在健康啮齿动物中分子激活DVC的Drp1足以诱导DVC线粒体裂变、ER应激和胰岛素抵抗。总之，这些数据表明，DVC中依赖Drp1的线粒体裂变变化调节胰岛素作用，并表明靶向大脑中依赖Drp1-线粒体的途径可能对胰岛素抵抗具有治疗潜力。
