Disruption of the circadian cycle is strongly associated with metabolic imbalance and reduced longevity in humans. Also, rodent models of circadian arrhythmia, such as the constitutive knockout of the clock gene Bmal1, leads to metabolic disturbances and early death. Although astrocyte clock regulates molecular and behavioral circadian rhythms, its involvement in the regulation of energy balance and lifespan is unknown. Here, we show that astrocyte-specific deletion of Bmal1 is sufficient to alter energy balance, glucose homeostasis, and reduce lifespan. Mutant animals displayed impaired hypothalamic molecular clock, age-dependent astrogliosis, apoptosis of hypothalamic astrocytes, and increased glutamate and GABA levels. Importantly, modulation of GABAA-receptor signaling completely restored glutamate levels, delayed the reactive gliosis as well as the metabolic phenotypes and expanded the lifespan of the mutants. Our results demonstrate that the astrocytic clock can influence many aspects of brain function and neurological disease and suggest astrocytes and GABAA receptor as pharmacological targets to prevent the metabolic dysfunctions and shortened lifespan associated with alterations of circadian rhythms.

中文翻译：

---

删除星形胶质细胞 BMAL1 会导致小鼠代谢失衡和寿命缩短。

昼夜节律周期的中断与代谢失衡和人类寿命缩短密切相关。此外，昼夜节律失常的啮齿动物模型，例如时钟基因 Bmal1 的组成性敲除，会导致代谢紊乱和过早死亡。虽然星形胶质细胞钟调节分子和行为昼夜节律，但其参与能量平衡和寿命的调节尚不清楚。在这里，我们表明 Bmal1 的星形胶质细胞特异性缺失足以改变能量平衡、葡萄糖稳态并缩短寿命。突变动物表现出下丘脑分子钟受损、年龄依赖性星形胶质细胞增生、下丘脑星形胶质细胞凋亡以及谷氨酸和 GABA 水平升高。重要的是，GABAA 受体信号的调节完全恢复了谷氨酸水平，延迟了反应性神经胶质增生以及代谢表型并延长了突变体的寿命。我们的研究结果表明，星形胶质细胞时钟可以影响大脑功能和神经系统疾病的许多方面，并建议将星形胶质细胞和 GABAA 受体作为药理学靶点，以防止与昼夜节律改变相关的代谢功能障碍和寿命缩短。