Abstract
The circadian clock is closely associated with energy metabolism. The liver clock can rapidly adapt to a new feeding cycle within a few days, whereas the lung clock is gradually entrained over one week. However, the mechanism underlying tissue-specific clock resetting is not fully understood. To characterize the rapid response to feeding cues in the liver clock, we examined the effects of a single time-delayed feeding on circadian rhythms in the liver and lungs of Per2::Luc reporter knockin mice. After adapting to a night-time restricted feeding schedule, the mice were fed according to a 4, 8, or 13 h delayed schedule on the last day. The phase of the liver clock was delayed in all groups with delayed feeding, whereas the lung clock remained unaffected. We then examined the acute response of clock and metabolism-related genes in the liver using focused DNA-microarrays. Clock mutant mice were bred under constant light to attenuate the endogenous circadian rhythm, and gene expression profiles were determined during 24 h of fasting followed by 8 h of feeding. Per2 and Dec1 were significantly increased within 1 h of feeding. Real-time RT-PCR analysis revealed a similarly acute response in hepatic clock gene expression caused by feeding wild type mice after an overnight fast. In addition to Per2 and Dec1, the expression of Per1 increased, and that of Rev-erbα decreased in the liver within 1 h of feeding after fasting, whereas none of these clock genes were affected in the lung. Moreover, an intraperitoneal injection of glucose combined with amino acids, but not either alone, reproduced a similar hepatic response. Our findings show that multiple clock genes respond to nutritional cues within 1 h in the liver but not in the lung.
Highlights
The mammalian circadian clock consists of a central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus and various oscillators in most peripheral tissues [1]
To understand the response of peripheral clocks induced by feeding cues, we examined the effects of a single delayed feeding on the circadian clocks in the liver and lungs
Our results showed that a single feeding and a single intraperitoneal injection of nutrients can efficiently induce an acute response of clock genes in the liver but not in the lung, and that a combination of glucose and amino acids is required for this response
Summary
The mammalian circadian clock consists of a central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus and various oscillators in most peripheral tissues [1]. The molecular oscillator of the circadian clock is thought to depend on a negative transcriptional feedback loop of core clock genes such as Per, Per, Cry, Cry, Clock and Bmal1 [2]. Restricted daytime feeding obviously entrains the circadian clocks of many peripheral tissues in nocturnal animals and even in extra-SCN brain regions, even though SCN activity is locked to LD cues [8,9,10]. The phases of circadian gene expression are shifted in most peripheral tissues after one week of daytime feeding, food-induced phase resetting proceeds faster in the liver than in the kidney, heart, pancreas or lung [8,9]. The molecular profile underlying the variable sensitivity of tissues to feeding cues and the nutrients required to affect the peripheral clocks remain obscure
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