Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan, China; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Healthcare Innovation Research Laboratory, Institute of Nursing Research & National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Cell Metab. 2024 Sep 3;36(9):1998-2014.e15. doi: 10.1016/j.cmet.2024.07.019. Epub 2024 Aug 19.
Sleep is essential for overall health, and its disruption is linked to increased risks of metabolic, cognitive, and cardiovascular dysfunctions; however, the molecular mechanisms remain poorly understood. This study investigated how sleep disturbances contribute to metabolic imbalance and cognition impairment using a chronic sleep fragmentation (SF) mouse model. SF mice exhibited impaired cognition, glucose metabolism, and insulin sensitivity compared with controls. We identified increased acetate levels in hypothalamic astrocytes as a defensive response in SF mice. Through acetate infusion or astrocyte-specific Acss1 deletion to elevate acetate levels, we observed mitigated metabolic and cognitive impairments in SF mice. Mechanistically, acetate binds and activates pyruvate carboxylase, thereby restoring glycolysis and the tricarboxylic acid cycle. Among individuals most commonly affected by SF, patients with obstructive sleep apnea exhibited elevated acetate levels when coupled with type 2 diabetes. Our study uncovers the protective effect of acetate against sleep-induced metabolic and cognitive impairments.
睡眠对于整体健康至关重要，其紊乱与代谢、认知和心血管功能障碍的风险增加有关；然而，其分子机制仍知之甚少。本研究使用慢性睡眠片段化（SF）小鼠模型，探讨了睡眠障碍如何导致代谢失衡和认知障碍。与对照组相比，SF 小鼠表现出认知功能受损、葡萄糖代谢和胰岛素敏感性降低。我们发现，SF 小鼠下丘脑星形胶质细胞中乙酸水平升高是一种防御反应。通过乙酸输注或星形胶质细胞特异性 Acss1 缺失来升高乙酸水平，我们观察到 SF 小鼠的代谢和认知损伤得到缓解。从机制上讲，乙酸结合并激活丙酮酸羧化酶，从而恢复糖酵解和三羧酸循环。在最常受 SF 影响的人群中，阻塞性睡眠呼吸暂停患者伴有 2 型糖尿病时，乙酸水平升高。我们的研究揭示了乙酸对睡眠引起的代谢和认知损伤的保护作用。
