酮体与睡眠：机制、临床前模型与人类证据的叙述性综述

文献信息

中文摘要

背景/目的： 睡眠是一种代谢动态状态，酮体可能作为氧化底物和信号代谢物与睡眠生理相互作用。β-羟丁酸（BHB）、乙酰乙酸（AcAc）和丙酮在禁食、碳水化合物限制、用于治疗或非治疗目的的生酮饮食、长时间运动、特定的胰岛素缺乏病理状态以及摄入外源性酮体后升高。本叙述性综述综合了机制、临床前和人类证据，将内源性产生的酮症和由外源性酮体摄入产生的酮症与睡眠结构、睡眠质量、睡眠呼吸障碍及睡眠相关代谢通路联系起来。
方法： 我们回顾了涉及生酮饮食、禁食或热量限制以及摄入外源性酮体的研究，优先考虑具有多导睡眠图、脑电图（EEG）、睡眠结构、呼吸或经验证的睡眠问卷结局的研究，同时也考虑关于神经元兴奋性、炎症、表观遗传调控、昼夜节律 timing 和脑能量代谢的机制研究。
结果： 最直接的临床前证据表明，AcAc（而非BHB）在小鼠非快速眼动（NREM）睡眠期间增加慢波活动（δ功率0.5-4 Hz）并抑制谷氨酸释放，支持酮代谢在睡眠稳态中的潜在作用。饮食、禁食和衰老模型进一步提示，脂质/酮代谢可改变NREM/快速眼动（REM）平衡、昼夜代谢节律以及对能量应激的睡眠-觉醒反应，老年大鼠数据显示生酮干预对REM和认知具有性别特异性效应。人类研究具有提示性但异质性较大：急性碳水化合物限制可在健康成人中增加慢波睡眠并减少REM睡眠；生酮治疗可能改善特定神经和代谢人群的主观睡眠；酮酯摄入可在剧烈晚间运动后改善睡眠效率，但在缺氧诱导的睡眠紊乱期间则不能。
结论： 酮体是与睡眠相关的代谢信号，但其效应是有条件的，而非普遍促进睡眠。它们还可能通过提高觉醒质量间接影响睡眠。与最佳睡眠结局相关的酮体浓度范围仍未确定，对睡眠的潜在剂量、时机和情境依赖性效应需要进一步研究。未来研究应区分AcAc与BHB生物学，测量夜间酮体动态，纳入PSG/EEG频谱终点，并将酮症特异性效应与体重减轻、能量缺乏、运动负荷、呼吸生理、昼夜节律 timing 和疾病相关混杂因素区分开来。

英文摘要

BACKGROUND/OBJECTIVES: Sleep is a metabolically dynamic state, and ketone bodies may interact with sleep physiology as both oxidative substrates and signaling metabolites. β-Hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone rise during fasting, carbohydrate restriction, ketogenic diets used for therapeutic or non-therapeutic purposes, prolonged exercise, selected pathological states of insulin deficiency, and after consumption of exogenous ketones. This narrative review synthesizes mechanistic, preclinical, and human evidence linking endogenously generated ketosis and ketosis generated from exogenous ketone consumption to sleep architecture, sleep quality, sleep-disordered breathing, and sleep-relevant metabolic pathways.
METHODS: We reviewed studies involving ketogenic diets, fasting or caloric restriction, and consumption of exogenous ketones, prioritizing investigations with polysomnography, electroencephalography (EEG), sleep architecture, respiratory, or validated sleep-questionnaire outcomes, while also considering mechanistic studies of neuronal excitability, inflammation, epigenetic regulation, circadian timing, and brain energetics.
RESULTS: The most direct preclinical evidence indicates that AcAc, but not BHB, increases slow-wave activity (delta power 0.5-4 Hz) during non-rapid eye movement (NREM) sleep and suppresses glutamate release in mice, supporting a potential role for ketone metabolism in sleep homeostasis. Dietary, fasting, and aging models further suggest that lipid/ketone metabolism can alter NREM/rapid eye movement (REM) balance, circadian metabolic rhythms, and sleep-wake responses to energetic stress, with aged-rat data showing sex-specific REM and cognitive effects of ketogenic interventions. Human studies are suggestive but heterogeneous: acute carbohydrate restriction can increase slow-wave sleep and reduce REM sleep in healthy adults; ketogenic therapies may improve subjective sleep in selected neurological and metabolic populations; and ketone ester ingestion can improve sleep efficiency after strenuous evening exercise, but not during hypoxia-induced sleep disruption.
CONCLUSIONS: Ketones are sleep-relevant metabolic signals, but their effects are conditional rather than universally sleep-promoting. They may also indirectly affect sleep by enhancing wakefulness quality. The ketone concentration range associated with optimal sleep outcomes remains undefined, and potential dose-, timing-, and context-dependent effects on sleep require further study. Future studies should distinguish AcAc from BHB biology, measure nocturnal ketone dynamics, incorporate PSG/EEG spectral endpoints, and separate ketosis-specific effects from weight loss, energy deficit, exercise load, respiratory physiology, circadian timing, and disease-related confounders.