Centre des Sciences du Goût et de l'Alimentation (CSGA), Université de Bourgogne, Dijon, France.
Antioxid Redox Signal. 2012 Aug 1;17(3):433-44. doi: 10.1089/ars.2011.4254. Epub 2012 Mar 6.
Hypothalamic mitochondrial reactive oxygen species (mROS)-mediated signaling has been recently shown to be involved in the regulation of energy homeostasis. However, the upstream signals that control this mechanism have not yet been determined. Here, we hypothesize that glucose-induced mitochondrial fission plays a significant role in mROS-dependent hypothalamic glucose sensing.
Glucose-triggered translocation of the fission protein dynamin-related protein 1 (DRP1) to mitochondria was first investigated in vivo in hypothalamus. Thus, we show that intracarotid glucose injection induces the recruitment of DRP1 to VMH mitochondria in vivo. Then, expression was transiently knocked down by intra-ventromedial hypothalamus (VMH) DRP1 siRNA (siDRP1) injection. 72 h post siRNA injection, brain intracarotid glucose induced insulin secretion, and VMH glucose infusion-induced refeeding decrease were measured, as well as mROS production. The SiDRP1 rats decreased mROS and impaired intracarotid glucose injection-induced insulin secretion. In addition, the VMH glucose infusion-induced refeeding decrease was lost in siDRP1 rats. Finally, mitochondrial function was evaluated by oxygen consumption measurements after DRP1 knock down. Although hypothalamic mitochondrial respiration was not modified in the resting state, substrate-driven respiration was impaired in siDRP1 rats and associated with an alteration of the coupling mechanism.
Collectively, our results suggest that glucose-induced DRP1-dependent mitochondrial fission is an upstream regulator for mROS signaling, and consequently, a key mechanism in hypothalamic glucose sensing. Thus, for the first time, we demonstrate the involvement of DRP1 in physiological regulation of brain glucose-induced insulin secretion and food intake inhibition. Such involvement implies DRP1-dependent mROS production.
最近的研究表明，下丘脑线粒体活性氧物质（mROS）介导的信号转导参与了能量稳态的调节。然而，控制这种机制的上游信号尚未确定。在这里，我们假设葡萄糖诱导的线粒体裂变在 mROS 依赖性下丘脑葡萄糖感应中起着重要作用。
首先在体内研究了葡萄糖触发的裂变蛋白 dynamin-related protein 1（DRP1）向线粒体的易位。因此，我们表明，颈内葡萄糖注射诱导 DRP1 在体内向 VMH 线粒体募集。然后，通过向腹内侧下丘脑（VMH）注射 DRP1 siRNA（siDRP1）瞬时敲低表达。siRNA 注射后 72 小时，测量脑内颈动脉葡萄糖诱导的胰岛素分泌和 VMH 葡萄糖输注诱导的再进食减少，以及 mROS 产生。SiDRP1 大鼠减少了 mROS，并损害了脑内颈动脉葡萄糖注射诱导的胰岛素分泌。此外，SiDRP1 大鼠失去了 VMH 葡萄糖输注诱导的再进食减少。最后，通过 DRP1 敲低后耗氧量测量评估线粒体功能。尽管下丘脑线粒体呼吸在静息状态下没有改变，但在 siDRP1 大鼠中，底物驱动的呼吸受损，并与偶联机制的改变有关。
总之，我们的结果表明，葡萄糖诱导的 DRP1 依赖性线粒体裂变是 mROS 信号的上游调节剂，因此是下丘脑葡萄糖感应的关键机制。因此，我们首次证明了 DRP1 参与了脑葡萄糖诱导的胰岛素分泌和食物摄入抑制的生理调节。这种参与意味着 DRP1 依赖性 mROS 产生。
