Schibler Ueli, Ripperger Juergen, Brown Steven A
Department of Molecular Biology, NCCR Frontiers in Genetics, University of Geneva, Sciences II, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland.
J Biol Rhythms. 2003 Jun;18(3):250-60. doi: 10.1177/0748730403018003007.
Peripheral cells from mammalian tissues, while perfectly capable of circadian rhythm generation, are not light sensitive and thus have to be entrained by nonphotic cues. Feeding time is the dominant zeitgeber for peripheral mammalian clocks: Daytime feeding of nocturnal laboratory rodents completely inverts the phase of circadian gene expression in many tissues, including liver, heart, kidney, and pancreas, but it has no effect on the SCN pacemaker. It is thus plausible that in intact animals, the SCN synchronizes peripheral docks primarily through temporal feeding patterns that are imposed through behavioral rest-activity cycles. In addition, body temperature rhythms, which are themselves dependent on both feeding patterns and rest-activity cycles, can sustain circadian, clock gene activity in vivo and in vitro. The SCN may also influence the phase of rhythmic gene expression in peripheral tissues through direct chemical pathways. In fact, many chemical signals induce circadian gene expression in tissue culture cells. Some of these have been shown to elicit phase shifts when injected into intact animals and are thus candidates for physiologically relevant timing cues. While the response of the SCN to light is strictly gated to respond only during the night, peripheral oscillators can be chemically phase shifted throughout the day. For example, injection of dexamethasone, a glucocorticoid receptor agonist, resets the phase of circadian liver gene expression during the entire 24-h day. Given the bewildering array of agents capable of influencing peripheral clocks, the identification of physiologically relevant agents used by the SCN to synchronize peripheral clocks will clearly be an arduous undertaking. Nevertheless, we feel that experimental systems by which this enticing problem can be tackled are now at hand.
哺乳动物组织的外周细胞虽然完全能够产生昼夜节律，但对光不敏感，因此必须通过非光信号进行调节。进食时间是外周哺乳动物生物钟的主要授时因子：夜间实验室啮齿动物在白天进食会完全颠倒包括肝脏、心脏、肾脏和胰腺在内的许多组织中昼夜节律基因表达的相位，但对视交叉上核（SCN）起搏器没有影响。因此，在完整动物中，SCN主要通过行为休息 - 活动周期所施加的时间进食模式来同步外周生物钟，这是合理的。此外，体温节律本身依赖于进食模式和休息 - 活动周期，它可以在体内和体外维持昼夜节律时钟基因的活性。SCN也可能通过直接的化学途径影响外周组织中节律性基因表达的相位。事实上，许多化学信号在组织培养细胞中诱导昼夜节律基因表达。其中一些已被证明注入完整动物时会引起相位变化，因此是生理相关定时信号的候选者。虽然SCN对光的反应严格限制在夜间，但外周振荡器在一整天内都可以通过化学方法进行相位改变。例如，注射地塞米松（一种糖皮质激素受体激动剂）可在整个24小时内重置昼夜节律肝脏基因表达的相位。鉴于能够影响外周生物钟的因子种类繁多，确定SCN用于同步外周生物钟的生理相关因子显然将是一项艰巨的任务。然而，我们认为现在已经有了可以解决这个诱人问题的实验系统。
