Chronobiology International ( IF 2.8 ) Pub Date : 2020-08-20 , DOI: 10.1080/07420528.2020.1796699 David B Allison 1 , Guang Ren 2 , Rodrigo A Peliciari-Garcia 3 , Sobuj Mia 4 , Graham R McGinnis 4 , Jennifer Davis 5 , Karen L Gamble 5 , Jeong-A Kim 2 , Martin E Young 4
ABSTRACT
Senescence-Accelerated Mouse-Prone 8 (SAMP8) mice exhibit characteristics of premature aging, including hair loss, cognitive dysfunction, reduced physical activity, impaired metabolic homeostasis, cardiac dysfunction and reduced lifespan. Interestingly, circadian disruption can induce or augment many of these same pathologies. Moreover, previous studies have reported that SAMP8 mice exhibit abnormalities in circadian wheel-running behavior, indicating possible alterations in circadian clock function. These observations led to the hypothesis that 24 h rhythms in behavior and/or circadian clock function are altered in SAMP8 mice and that these alterations may contribute to perturbations in whole-body metabolism. Here, we report that 6-month-old SAMP8 mice exhibit a more prominent biphasic pattern in daily behaviors (food intake and physical activity) and whole-body metabolism (energy expenditure, respiratory exchange ratio), relative to SAMR1 control mice. Consistent with a delayed onset of food intake at the end of the light phase, SAMP8 mice exhibit a phase delay (1.3–1.9 h) in 24 h gene expression rhythms of major circadian clock components (bmal1, rev-erbα, per2, dbp) in peripheral tissues (liver, skeletal muscle, white adipose tissue [WAT], brown adipose tissue [BAT]). Forcing mice to consume food only during the dark period improved alignment of both whole-body metabolism and oscillations in expression of clock genes in peripheral tissues between SAMP8 and SAMR1 mice. Next, interrogation of metabolic genes revealed altered expression of thermogenesis mediators (ucp1, pgc1α, dio2) in WAT and/or BAT in SAMP8 mice. Interestingly, SAMP8 mice exhibit a decreased tolerance to an acute (5 h) cold challenge. Moreover, SAMP8 and SAMR1 mice exhibited differential responses to a chronic (1 week) decrease in ambient temperature; the greatest response in whole-body substrate selection was observed in SAMR1 mice. Collectively, these observations reveal differential behaviors (e.g. 24 h food intake patterns) in SAMP8 mice that are associated with perturbations in peripheral circadian clocks, metabolism and thermogenesis.
中文翻译:
加速衰老的小鼠模型中的昼夜、代谢和产热变化。
摘要
Senescence-Accelerated Mouse-Prone 8 (SAMP8) 小鼠表现出过早衰老的特征,包括脱发、认知功能障碍、体力活动减少、代谢稳态受损、心脏功能障碍和寿命缩短。有趣的是,昼夜节律紊乱可以诱发或增加许多相同的病症。此外,先前的研究报道 SAMP8 小鼠表现出昼夜节律轮运行行为异常,表明昼夜节律功能可能发生改变。这些观察导致假设 SAMP8 小鼠的行为和/或生物钟功能的 24 小时节律发生了改变,并且这些改变可能导致全身代谢的扰动。这里,我们报告说,与 SAMR1 对照小鼠相比,6 个月大的 SAMP8 小鼠在日常行为(食物摄入和身体活动)和全身代谢(能量消耗、呼吸交换率)方面表现出更突出的双相模式。与光照期结束时食物摄入的延迟开始一致,SAMP8 小鼠在主要生物钟成分的 24 小时基因表达节律中表现出相位延迟(1.3-1.9 小时)。bmal1,rev-erbα,per2,dbp)在外周组织(肝脏、骨骼肌、白色脂肪组织 [WAT]、棕色脂肪组织 [BAT])中。强迫小鼠仅在黑暗时期进食可以改善 SAMP8 和 SAMR1 小鼠之间的全身代谢和外周组织中时钟基因表达的波动。接下来,对代谢基因的询问揭示了产热介质(ucp1、pgc1α、dio2) 在 SAMP8 小鼠的 WAT 和/或 BAT 中。有趣的是,SAMP8 小鼠对急性(5 小时)冷挑战的耐受性降低。此外,SAMP8 和 SAMR1 小鼠对环境温度的慢性(1 周)降低表现出不同的反应。在 SAMR1 小鼠中观察到全身底物选择的最大反应。总的来说,这些观察结果揭示了 SAMP8 小鼠的不同行为(例如 24 小时食物摄入模式),这些行为与外周生物钟、新陈代谢和产热的扰动有关。