Circadian Desynchrony Promotes Metabolic Disruption in a Mouse Model of Shiftwork

Shiftwork is associated with adverse metabolic pathophysiology, and the rising incidence of shiftwork in modern societies is thought to contribute to the worldwide increase in obesity and metabolic syndrome. The underlying mechanisms are largely unknown, but may involve direct physiological effects of nocturnal light exposure, or indirect consequences of perturbed endogenous circadian clocks. This study employs a two-week paradigm in mice to model the early molecular and physiological effects of shiftwork. Two weeks of timed sleep restriction has moderate effects on diurnal activity patterns, feeding behavior, and clock gene regulation in the circadian pacemaker of the suprachiasmatic nucleus. In contrast, microarray analyses reveal global disruption of diurnal liver transcriptome rhythms, enriched for pathways involved in glucose and lipid metabolism and correlating with first indications of altered metabolism. Although altered food timing itself is not sufficient to provoke these effects, stabilizing peripheral clocks by timed food access can restore molecular rhythms and metabolic function under sleep restriction conditions. This study suggests that peripheral circadian desynchrony marks an early event in the metabolic disruption associated with chronic shiftwork. Thus, strengthening the peripheral circadian system by minimizing food intake during night shifts may counteract the adverse physiological consequences frequently observed in human shift workers.

轮班工作与不良代谢病理生理改变密切相关，现代社会中轮班工作发生率的持续攀升，被认为是全球肥胖与代谢综合征（metabolic syndrome）患病率上升的关键驱动因素之一。其潜在致病机制目前尚未完全明确，可能涉及夜间光照暴露的直接生理效应，或是内源性昼夜节律时钟紊乱引发的间接后果。本研究以小鼠为模型，构建为期两周的实验范式，模拟轮班工作带来的早期分子与生理影响。两周定时睡眠限制，对小鼠视交叉上核（suprachiasmatic nucleus）这一中枢昼夜节律起搏点的昼夜活动模式、摄食行为以及时钟基因调控均产生轻度影响。与之相对，基因芯片（microarray）分析显示，小鼠肝脏的昼夜转录组（transcriptome）节律出现全局性紊乱，该紊乱富集于糖代谢与脂代谢相关通路，且与代谢改变的早期指征存在相关性。尽管仅改变进食时间本身不足以引发上述效应，但通过定时进食以稳定外周昼夜节律时钟，可在睡眠限制条件下恢复分子节律与代谢功能。本研究表明，外周昼夜节律失同步是慢性轮班工作相关代谢紊乱的早期标志性事件。因此，在夜间轮班期间通过限制进食以强化外周昼夜节律系统，或可抵消人类轮班工作者常出现的不良生理后果。