Glucagon-CREB/CRTC2 Signaling Cascade Regulates Hepatic BMAL1 Protein

Dec 7, 2014The Journal of biological chemistry

Glucagon signaling controls liver BMAL1 protein through CREB and CRTC2 pathways

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Abstract

Fasting and refeeding hormones regulate the expression of Bmal1, a key gene in the circadian clock, in the liver.

Glucagon activates a transcriptional complex during fasting that enhances Bmal1 expression.
CRTC2 is essential for the basal regulation of Bmal1 transcription.
Insulin inhibits fasting-induced Bmal1 expression by blocking CRTC2 activity during refeeding.
CRTC2 may play a crucial role in linking the circadian clock with energy metabolism.

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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.

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Glucagon-CREB/CRTC2 Signaling Cascade Regulates Hepatic BMAL1 Protein

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