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.

背侧迷走神经复合体 (DVC) 感知胰岛素并控制葡萄糖稳态、摄食行为和体重。大鼠三天的高脂饮食 (HFD) 足以诱导 DVC 中的胰岛素抵抗并削弱其调节摄食行为的能力。HFD 喂养与 DVC 中增加的动力相关蛋白 1 (Drp1) 依赖性线粒体裂变有关。尽管控制体重的确切机制仍然难以捉摸，但较高的 Drp1 活性会抑制胰岛素信号传导。我们表明 DVC 中的 Drp1 激活增加了大鼠的体重增加，而 HFD 喂养的大鼠中的 Drp1 抑制减少了食物摄入、体重增加和脂肪组织。在 DVC 中表达活性 Drp1 的大鼠具有更高水平的诱导型一氧化氮合酶 (iNOS)，并且在 HFD 喂养的大鼠中敲低 DVC iNOS 导致食物摄入减少，体重增加和脂肪组织。最后，抑制 DVC 星形胶质细胞中的线粒体裂变足以保护大鼠免受 HFD 依赖性胰岛素抵抗、摄食过多、体重增加和脂肪沉积。我们发现了大脑调节全身代谢的新分子和细胞靶点，这可以为对抗肥胖和糖尿病的新策略提供信息。