Abstract
Energy metabolism follows a diurnal pattern responding to the cycles of light and food exposures. Although food availability is a potent synchronizer of peripheral circadian clock in mammals, the underlying mechanism remains elusive. Here, we found that the temporal signals of fasting and refeeding hormones regulate the transcription of Bmal1, a key transcription activator of molecular clock, in the liver. During fasting, glucagon, a major fasting hormone, activates CREB/CRTC2 transcriptional complex that is recruited to Bmal1 promoter to induce its expression. Furthermore, we showed that CRTC2 is required for basal transcriptional regulation of Bmal1 by experiments using either adenovirus-mediated CRTC2 RNAi knockdown or primary Crtc2 null hepatocytes. On the other hand, insulin suppresses fasting-induced Bmal1 expression by inhibiting CRTC2 activity after refeeding. Taken together, our results indicate CRTC2 as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.
Highlights
The role of glucagon in regulation of hepatic circadian clock is unclear
Considering the temporal variations in the diurnal cycles of clock gene expression and hormonal signaling, we reexamined the transcriptional responses of circadian clock genes, including Bmal1, Clock, Per1, Cry1, Nr1d1, and gluconeogenic gene Pck1, as a positive control to fasting and refeeding in livers from mice fasted from ZT12
We demonstrated that glucagon stimulates the expression of Bmal1 through activating the cAMP-response element-binding protein (CREB) coactivator CREB-regulated transcriptional coactivator 2 (CRTC2), which is essential for maintaining normal circadian rhythms
Summary
Results: Glucagon-CREB/CRTC2 signaling axis plays an important role in regulation of hepatic Bmal expression. Conclusion: We find that the temporal signals of fasting and refeeding hormones regulate the transcription of Bmal in the liver. Significance: We identify a novel transcriptional pathway that links glucagon/insulin metabolic cues and circadian clock. We found that the temporal signals of fasting and refeeding hormones regulate the transcription of Bmal, a key transcription activator of molecular clock, in the liver. Glucagon, a major fasting hormone, activates CREB/CRTC2 transcriptional complex that is recruited to Bmal promoter to induce its expression. Insulin suppresses fasting-induced Bmal expression by inhibiting CRTC2 activity after refeeding. Our results indicate CRTC2 as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism
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