Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain
Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain
复制标题
抑制背侧迷走神经复合体中的线粒体裂变和 iNOS 可防止暴饮暴食和体重增加
DOI：
10.1101/2020.06.26.173641
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Patel B
中科院分区：
文献类型：
--
作者：
Patel B
背侧迷走神经复合体(DVC)感知胰岛素，控制血糖稳态、摄食行为和体重。大鼠三天的高脂饮食(HFD)足以在DVC中诱导胰岛素抵抗，并削弱其调节摄食行为的能力。HFD摄取与DVC中依赖动力蛋白相关蛋白1(Drp1)的线粒体分裂增加有关。更高的Drp1活性抑制胰岛素信号传递，尽管控制体重的确切机制仍然难以捉摸。我们发现，DVC中的Drp1激活增加了大鼠的体重增加，而抑制HFD喂养的大鼠的Drp1减少了食物的摄入量、体重增加和脂肪组织。在DVC中表达活性Drp1的大鼠具有更高的诱导型一氧化氮合酶(INOS)水平，而高脂饲料喂养的DVC中iNOS的下调导致摄食量、体重增加和脂肪组织的减少。最后，抑制DVC星形胶质细胞的线粒体分裂足以保护大鼠免受高脂依赖的胰岛素抵抗、过度吞噬、体重增加和脂肪沉积的影响。我们发现了大脑调节全身代谢的新分子和细胞靶点，这可能会为抗击肥胖和糖尿病的新策略提供信息。
The dorsal vagal complex (DVC) senses insulin and controls glucose homeostasis, feeding behaviour and bodyweight. Three-days of high-fat diet (HFD) in rats are sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in the DVC. Higher Drp1 activity inhibits insulin signalling, although the exact mechanisms controlling bodyweight remain elusive. We show that Drp1 activation in DVC increases weight gain in rats and Drp1 inhibition in HFD-fed rats reduced food intake, weight gain and adipose tissue. Rats expressing active Drp1 in the DVC had higher levels of inducible nitric oxide synthase (iNOS) and knockdown of DVC iNOS in HFD-fed rats led to a reduction in food intake, weight gain and adipose tissue. Finally, inhibiting mitochondrial fission in DVC astrocytes was sufficient to protect rats from HFD-dependent insulin resistance, hyperphagia, weight gain and fat deposition. We uncovered new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.