Leiden University Medical Center, Department of Molecular Cell Biology, Laboratory of Neurophysiology, Bldg. 2, Room T5-32, Einthovenweg 20, PO Box 9600, 2300 RC Leiden, the Netherlands.
FASEB J. 2013 Apr;27(4):1721-32. doi: 10.1096/fj.12-210898. Epub 2013 Jan 9.
Circadian rhythm disturbances are observed in, e.g., aging and neurodegenerative diseases and are associated with an increased incidence of obesity and diabetes. We subjected male C57Bl/6J mice to constant light [12-h light-light (LL) cycle] to examine the effects of a disturbed circadian rhythm on energy metabolism and insulin sensitivity. In vivo electrophysiological recordings in the central pacemaker of the suprachiasmatic nuclei (SCN) revealed an immediate reduction in rhythm amplitude, stabilizing at 44% of normal amplitude values after 4 d LL. Food intake was increased (+26%) and energy expenditure decreased (-13%), and we observed immediate body weight gain (d 4: +2.4%, d 14: +5.0%). Mixed model analysis revealed that weight gain developed more rapidly in response to LL as compared to high fat. After 4 wk in LL, the circadian pattern in feeding and energy expenditure was completely lost, despite continuing low-amplitude rhythms in the SCN and in behavior, whereas weight gain had stabilized. Hyperinsulinemic-euglycemic clamp analysis revealed complete abolishment of normal circadian variation in insulin sensitivity in LL. In conclusion, a reduction in amplitude of the SCN, to values previously observed in aged mice, is sufficient to induce a complete loss of circadian rhythms in energy metabolism and insulin sensitivity.
昼夜节律紊乱可见于衰老和神经退行性疾病等情况，并且与肥胖症和糖尿病发病率的增加有关。我们让雄性 C57Bl/6J 小鼠处于持续光照[12 小时光照-12 小时黑暗（LL）周期]下，以检查昼夜节律紊乱对能量代谢和胰岛素敏感性的影响。在视交叉上核（SCN）的中枢起搏器中的体内电生理记录显示，节律幅度立即减小，在持续 LL 4 天后稳定在正常幅度值的 44%。食物摄入量增加（增加 26%），能量消耗减少（减少 13%），我们观察到体重立即增加（第 4 天：增加 2.4%，第 14 天：增加 5.0%）。混合模型分析表明，与高脂肪相比，LL 引起的体重增加发展得更快。在 LL 中 4 周后，尽管 SCN 和行为中仍存在低幅度节律，但摄食和能量消耗的昼夜节律模式完全丧失，而体重增加则已稳定。高胰岛素-正常血糖钳夹分析显示，LL 中胰岛素敏感性的正常昼夜变化完全消失。总之，SCN 幅度的降低，达到以前在老年小鼠中观察到的值，足以诱导能量代谢和胰岛素敏感性的昼夜节律完全丧失。
