Liver cells control our biological clock

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The "humanized" mouse model receives liver cells from normal mice (con
The "humanized" mouse model receives liver cells from normal mice (control animals) or human liver cells (humanized mice). The presence of human liver cells leads to a modification of the circadian clock of the liver, the muscle and affects the central clock (the suprachiasmatic nucleus, SCN) which results in a phase advance "shift of the circadian rhythms" in the humanized animal which sees its metabolism and its behaviors advanced by a few hours. Luquet et al / Science Advances
The liver may influence the body’s central biological clock, a group of brain cells that influence most physiological and behavioral aspects.

Our liver partly controls our central biological clock, according to scientists from CNRS and Université Paris Cité. Their study, to be published on May 17, 2023 in the journal Science Advances, has indeed shown that it was possible to shift the biological clock of mice by introducing human liver cells into their liver.

The biological or circadian clock allows organisms to regulate their activity according to the daily cycle. It relies on the action of a central clock, represented by a group of brain cells, the suprachiasmatic nucleus, which synchronizes the circadian clocks of all organs, called peripheral clocks. Until now, the synchronization of the circadian cycle in mammals was seen as a one-way mechanism, under the exclusive control of the suprachiasmatic nuclei towards the peripheral clocks.

However, scientists from the CNRS, Université Paris Cité 1 and the University of Queensland 2 , as part of a European collaborative project 3 , have just shown that the liver also has an influence on peripheral clocks. By studying a line of chimeric mice whose livers are composed of human hepatocytes, they observed that these usually nocturnal animals showed a two-hour shift in their daily cycle.

The mice activated and started feeding two hours before nightfall: they had become partly diurnal. For the researchers, this shift would be the result of the human liver cells present in this chimeric animal model taking control of the mouse’s central clock. They would thus be able to affect the peripheral clocks of the different organs.

These results suggest that a change in liver rhythms, for example during liver diseases such as cirrhosis, could affect the synchronization action of the central clock. This in turn could affect the entire circadian physiology, including the sleep/wake cycle, and contribute to the development of metabolic pathologies. This discovery also implies that a restoration of the disturbed liver cycles could have benefits for the whole organism. The hormonal or nervous mechanisms of this dialogue between brain, liver and circadian clock remain to be identified.

3 Study conducted within the framework of the European consortium Health and the Understanding of Metabolism, Aging and Nutrition (EU- HUMAN)

Bibliography

Mice with humanized livers reveal the role of hepatocyte clocks in rhythmic behavior. Anne-Sophie Delbès, Mar Quiñones, Cédric Gobet, Julien Castel, Raphaël G. P Denis, Jérémy Berthelet, Benjamin D. Weger, Etienne Challet, Aline Charpagne, Sylviane Metairon, Julie Piccand, Marine Kraus, Bettina H. Rohde, John Bial, Elizabeth M. Wilson, Lise-Lotte Vedin, Mirko E. Minniti, Matteo Pedrelli, Paolo Parini, Frédéric Gachon and Serge Luquet. Science Advances, May 17, 2023.

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