Astrocytes represent central regulators of brain glucose metabolism and neuronal function. They have recently been shown to adapt their function in response to alterations in nutritional state through responding to the energy state-sensing hormones leptin and insulin. Here, we demonstrate that glucagon-like peptide (GLP)-1 inhibits glucose uptake and promotes β-oxidation in cultured astrocytes. Conversely, postnatal GLP-1 receptor (GLP-1R) deletion in glial fibrillary acidic protein (GFAP)-expressing astrocytes impairs astrocyte mitochondrial integrity and activates an integrated stress response with enhanced fibroblast growth factor (FGF)21 production and increased brain glucose uptake. Accordingly, central neutralization of FGF21 or astrocyte-specific FGF21 inactivation abrogates the improvements in glucose tolerance and learning in mice lacking GLP-1R expression in astrocytes. Collectively, these experiments reveal a role for astrocyte GLP-1R signaling in maintaining mitochondrial integrity, and lack of GLP-1R signaling mounts an adaptive stress response resulting in an improvement of systemic glucose homeostasis and memory formation.

星形胶质细胞代表大脑葡萄糖代谢和神经元功能的中央调节剂。最近已显示它们通过响应能量状态感应激素瘦素和胰岛素来调整其功能以响应营养状态的变化。在这里，我们证明胰高血糖素样肽 (GLP)-1 抑制葡萄糖摄取并促进培养的星形胶质细胞中的 β-氧化。相反，表达胶质纤维酸性蛋白 (GFAP) 的星形胶质细胞中的出生后 GLP-1 受体 (GLP-1R) 缺失会损害星形胶质细胞线粒体完整性并激活综合应激反应，增强成纤维细胞生长因子 (FGF)21 的产生和增加脑葡萄糖摄取。因此，FGF21 的中和或星形胶质细胞特异性 FGF21 失活消除了星形胶质细胞中缺乏 GLP-1R 表达的小鼠的葡萄糖耐量和学习的改善。总的来说，这些实验揭示了星形胶质细胞 GLP-1R 信号在维持线粒体完整性中的作用，缺乏 GLP-1R 信号会引发适应性应激反应，从而改善全身葡萄糖稳态和记忆形成。