Mice with humanized livers reveal the involvement of hepatocyte circadian clocks in the phase entrainment of rhythmic behavior and physiology

The circadian clock represents an evolutionarily acquired gene network that synchronizes physiology to anticipate environmental changes caused by the succession of day and night. While most mammalian cells have a circadian clock, their synchronization depends on a central pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus that integrates light signals. While peripheral organs can be also synchronized by feeding cues and can be uncoupled from the central pacemaker, no impact of peripheral organs on the central clock has been yet observed. Here, we used a mouse chimeric model in which mouse hepatocytes have been replaced by human hepatocytes that have different circadian and signaling properties to characterize such potential feedback. Remarkably, we observed that liver humanization rewired the liver diurnal gene expression and advance the circadian clock by approximately 4 hours. Strikingly, this phase advance was also observed in the muscle and for the entire rhythmic physiology of the animals, with an impact of human hepatocytes on the circadian function of the central clock. Like mice with a deficient central clock, the humanized animals shifted their physiology more rapidly to the light phase under day feeding. This data prompt to reconsider the role of peripheral clocks on the central pacemaker and offers new perspective to understand the impact of diseased organs on the global circadian physiology. RNA-seq from chimeric mice implemented with mouse/human hepatocytes, sampled around the clock in liver, muscle, arcuate nucleus, and suprachiasmatic nucleus.