Diet-Induced Glial Insulin Resistance Impairs The Clearance Of Neuronal Debris.
Diet-Induced Glial Insulin Resistance Impairs The Clearance Of Neuronal Debris.
复制标题
饮食引起的神经胶质胰岛素抵抗会损害神经元碎片的清除。
DOI：
10.1101/2023.03.09.531940
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Rajan,Akhila
中科院分区：
文献类型：
--
作者：
Alassaf,Mroj;Rajan,Akhila
肥胖会显著增加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。神经胶质吞噬功能的缺陷是神经退行性疾病的关键特征，因为神经元碎片的延迟清除可导致炎症、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，体重和全身代谢，这表明饮食可能在调节神经胶质功能中发挥作用。虽然认识到神经胶质细胞是胰岛素敏感的，但致肥胖饮食是否能诱导神经胶质胰岛素抵抗并由此损害神经胶质吞噬功能仍然是未知的。在这里，使用果蝇模型，我们表明，慢性致肥胖饮食诱导神经胶质胰岛素抵抗和损害清除神经元碎片。具体来说，致胖饮食暴露下调了胶质细胞相关吞噬受体德雷珀的基础表达和损伤诱导的表达。果蝇胰岛素产生细胞（IPC）系统性胰岛素释放的组成性激活模拟饮食诱导的肥胖对神经胶质德雷珀表达的影响。与此相反，从IPC的遗传衰减全身胰岛素释放拯救饮食诱导的神经胶质细胞胰岛素抵抗和德雷珀表达。值得注意的是，我们发现，遗传刺激磷脂酰肌醇3-激酶（PI 3 K），胰岛素受体信号的下游效应，拯救了HSD-induced胶质缺陷。因此，我们建立了致肥胖饮食损害神经胶质吞噬功能，并延迟神经元碎片的清除。
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 downregulates 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 signaling, rescues HSD-induced glial defects. Hence, we establish that obesogenic diets impair glial phagocytic function and delays the clearance of neuronal debris.