Mice with humanized livers reveal the role of hepatocyte clocks in rhythmic behavior

Jun 17, 2023 | Central Control of Feeding Behaviour and Energy Expenditure, Diabetes Institute, METABOL’IC Platform for the analysis of metabolism from the cell to the small animal, Publications

An article by Anne-Sophie Delbès, Mar Quiñones, CédricGobet, JulienCastel, Raphaël G. P. Denis, JérémyBerthelet, 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, Serge Luquet

Engraftment of human hepatocyte affects liver rhythmic gene expression.
(A) Model for humanized Fah−/−, Rag2−/−, Il2rg−/− (FRG-KO) that can be repopulated with primary human (red) or murine (black) hepatocytes to produce LHM or LMM mice. (B) Experimental design for liver tissue collection before RNA extraction, sequencing, and analysis according to gene expression rhythmic properties. Alteration of rhythmic gene expression of murine transcript in the liver of LMM  and both murine (black, Mu-RNA) and human transcript (red, Hu-RNA) in the liver of LHM mice is assessed by model selection (models 1 to 15): black line, stable transcription; black wave, rhythmic transcription; red or green waves, rhythmic profiles with different rhythmic parameters (i.e., phase and/or amplitude). (C) Heatmaps of normalized rhythmic mRNA levels (BICW > 0.3, log2 amplitude > 0.5) in the liver of LMM (black) and LHM (black) murine and human transcript (red) in the liver of LMM and LHM. RNA presented here belonged to model 4 where genes were rhythmic only in LMM. (D) Radial plot of the distribution peak phase of expression for genes rhythmic only in the liver of LMM

Abstract

The synchronization of circadian clock depends on a central pacemaker located in the suprachiasmatic nuclei. However, the potential feedback of peripheral signals on the central clock remains poorly characterized. To explore whether peripheral organ circadian clocks may affect the central pacemaker, we used a chimeric model in which mouse hepatocytes were replaced by human hepatocytes. Liver humanization led to reprogrammed diurnal gene expression and advanced the phase of the liver circadian clock that extended to muscle and the entire rhythmic physiology. Similar to clock-deficient mice, liver-humanized mice shifted their rhythmic physiology more rapidly to the light phase under day feeding. Our results indicate that hepatocyte clocks can affect the central pacemaker and offer potential perspectives to apprehend pathologies associated with altered circadian physiology.

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Diabetes Institute scientific day

Diabetes Institute scientific day

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The overall goal of this Diabetes Institute scientific day is to provide the most important and up-to-date research in the field of metabolism made at University Paris Cité. The workshop will focus on understanding the recent progress in adipose tissue and liver biology including metabolic and inflammatory processes in the control of the energy homeostasis. Special emphasis will be done to highlight the importance of the organ crosstalk and how signaling pathways in one tissue could affect the metabolism in other tissue.