Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain.
Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain.
复制标题
DOI：
10.1371/journal.pbio.3002359
复制
发表时间：
2023-11
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
肥胖显著增加了患神经退行性疾病的风险，但这种联系背后的确切机制仍不清楚。神经胶质细胞吞噬功能缺陷是神经退行性疾病的关键特征，因为神经元碎片清除延迟可导致炎症、神经元死亡和神经系统恢复不良。越来越多的证据表明，神经胶质功能可以影响摄食行为、体重和系统代谢，提示饮食可能在调节神经胶质功能中发挥作用。虽然人们认识到神经胶质细胞是胰岛素敏感的，但肥胖饮食是否会诱导神经胶质细胞胰岛素抵抗，从而损害神经胶质细胞的吞噬功能仍不清楚。在这里，使用果蝇模型，我们证明了慢性肥胖饮食诱导了神经胶质胰岛素抵抗，并损害了神经元碎片的清除。具体地说，肥胖饮食暴露下调了基础和损伤诱导的胶质细胞相关吞噬细胞受体Draper的表达。果蝇胰岛素产生细胞(IPC)系统性胰岛素释放的结构性激活模拟了饮食诱导的肥胖对胶质Draper表达的影响。相反，从基因上减少胰岛素分泌可以挽救饮食诱导的神经胶质细胞胰岛素抵抗和Draper的表达。值得注意的是，我们表明，基因刺激的磷脂酰肌醇3-激酶(PI3K)，胰岛素受体(IR)信号的下游效应者，拯救了高糖饮食(HSD)诱导的胶质细胞缺陷。因此，我们确定肥胖饮食损害了神经胶质细胞的吞噬功能，并延迟了神经元碎片的清除。这项研究表明，肥胖饮食会导致果蝇成年大脑中的小胶质细胞胰岛素抵抗，直接扰乱胶质细胞维持健康神经元微环境的能力。这为肥胖引起的胰岛素抵抗和神经退行性疾病之间的因果联系提供了一个机械的洞察力。
Obesity significantly increases the risk of developing neurodegenerative disorders, yet the precise mechanisms underlying this connection remain unclear. Defects in glial phagocytic function are a key feature of neurodegenerative disorders, as delayed clearance of neuronal debris can result in inflammation, neuronal death, and poor nervous system recovery. Mounting evidence indicates that glial function can affect feeding behavior, weight, and systemic metabolism, suggesting that diet may play a role in regulating glial function. While it is appreciated that glial cells are insulin sensitive, whether obesogenic diets can induce glial insulin resistance and thereby impair glial phagocytic function remains unknown. Here, using a Drosophila model, we show that a chronic obesogenic diet induces glial insulin resistance and impairs the clearance of neuronal debris. Specifically, obesogenic diet exposure down-regulates the basal and injury-induced expression of the glia-associated phagocytic receptor, Draper. Constitutive activation of systemic insulin release from Drosophila insulin-producing cells (IPCs) mimics the effect of diet-induced obesity on glial Draper expression. In contrast, genetically attenuating systemic insulin release from the IPCs rescues diet-induced glial insulin resistance and Draper expression. Significantly, we show that genetically stimulating phosphoinositide 3-kinase (Pi3k), a downstream effector of insulin receptor (IR) signaling, rescues high-sugar diet (HSD)-induced glial defects. Hence, we establish that obesogenic diets impair glial phagocytic function and delays the clearance of neuronal debris. This study shows that an obesogenic diet causes microglial insulin resistance in the Drosophila adult brain, directly disrupting the ability of glia to maintain a healthy neuronal microenvironment. This provides a mechanistic insight into the causative link between obesity-induced insulin resistance and neurodegenerative disorders.