Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
J Biol Rhythms. 2011 Jun;26(3):230-40. doi: 10.1177/0748730411405958.
The mammalian circadian clock is known to be entrained by both a daily light-dark cycle and daily feeding cycle. However, the mechanisms of feeding-induced entrainment are not as fully understood as those of light entrainment. To elucidate the first step of entrainment of the liver clock, we identified the circadian clock gene(s) that show both phase advance and acute change of gene expression during the early term of the daytime refeeding schedule in mice. The expressions of liver Per2 and Rev-erbα genes were phase-advanced within 1 day of refeeding. Additionally, the upregulation of Per2 mRNA and down-regulation of Rev-erbα mRNA were induced within 2 hours, not only by food intake but also by insulin injection in intact mice. These expression changes by food intake were not revealed in streptozotocin-treated insulin-deficient mice, but insulin injection was able to recover the impairment of Per2 and Rev-erbα gene expression. Furthermore, we demonstrated using an ex vivo luciferase monitoring system that insulin injection during the daytime causes a phase advance of liver Per2 expression rhythm in Per2::luciferase knock-in mice. In embryonic fibroblasts from Per2::luciferase knock-in mice, insulin infusion caused an acute increase of Per2 gene expression and a similar phase advance of Per2 expression rhythm. Our results indicate that an acute change of Per2 and Rev-erbα gene expression mediated by refeeding-induced insulin secretion is a critical step mediating the early phase of feeding-induced entrainment of the liver clock.
哺乳动物的生物钟不仅受到每日光暗周期的调节，还受到每日进食周期的调节。然而，进食诱导的同步机制并不像光诱导的同步机制那样被完全理解。为了阐明肝脏时钟同步的第一步，我们鉴定了在小鼠白天重新喂食时间表的早期，显示出相位提前和基因表达急性变化的昼夜节律基因。肝脏 Per2 和 Rev-erbα 基因的表达在重新喂食的 1 天内就出现了相位提前。此外，在完整小鼠中，不仅通过进食，而且通过胰岛素注射，在 2 小时内就诱导了 Per2 mRNA 的上调和 Rev-erbα mRNA 的下调。这些由进食引起的表达变化在链脲佐菌素处理的胰岛素缺乏小鼠中没有显示出来，但胰岛素注射能够恢复 Per2 和 Rev-erbα 基因表达的损伤。此外，我们使用体外荧光素酶监测系统证明，白天胰岛素注射会导致 Per2::荧光素酶敲入小鼠肝脏 Per2 表达节律的相位提前。在 Per2::荧光素酶敲入小鼠的胚胎成纤维细胞中，胰岛素输注引起 Per2 基因表达的急性增加和 Per2 表达节律的类似相位提前。我们的结果表明，由重新喂食诱导的胰岛素分泌介导的 Per2 和 Rev-erbα 基因表达的急性变化是介导肝脏时钟进食诱导同步的早期阶段的关键步骤。
