高脂饮食（HFD）导致的下丘脑胶质增生增加了对食欲过盛和体重增加的易感性。然而，微胶质细胞对葡萄糖调控的体重无关贡献尚未确定。在这里，我们展示了通过细胞特异性IKKβ基因缺失来减少微胶质细胞核因子κB（NF-κB）信号通路引起的糖耐量降低，尽管体重和脂肪含量减少。相反，通过删除NF-κB信号通路抑制剂和通过修饰的Gq型胆碱能受体的化学遗传激活，两种基因方法增强了微胶质细胞的促炎信号传导，在瘦小鼠和肥胖小鼠中改善了葡萄糖耐受性，而与饮食无关。微胶质细胞对葡萄糖稳态的调节涉及一种肿瘤坏死因子α（TNF-α）依赖的机制，该机制增加了下丘脑葡萄糖感知神经元以及其他神经元的前儿茶酚醛肽原（POMC）的激活，最终通过副交感神经途径引起首相胰岛素分泌的显著增加。总体而言，这些结果表明微胶质细胞以一种与体重无关的方式调节葡萄糖稳态，这是一种减轻与肥胖相关的葡萄糖耐受性恶化的意外机制。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.Copyright © 2023 Elsevier Inc. All rights reserved.