Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver

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    The authors report that, in the murine liver, intermittent fasting alters the homeostatic regenerative programme. This has fundamental implications for the use of murine models to study liver regeneration and cancer and highlights through a series of solid mechanistic studies the role of FGF/Wnt signalling interactions in modulating fasted associated regeneration. It opens up further questions as to why this occurs, how this is beneficial to adapting to a fasting state, and the potential for translation.

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Abstract

Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary changes influence liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF-induced hepatocyte proliferation is driven by the combined action of systemic FGF15 and localized WNT signaling. Hepatocyte proliferation during periods of fasting and re-feeding re-establishes a constant liver-to-body mass ratio, thus maintaining the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.

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  1. eLife assessment

    The authors report that, in the murine liver, intermittent fasting alters the homeostatic regenerative programme. This has fundamental implications for the use of murine models to study liver regeneration and cancer and highlights through a series of solid mechanistic studies the role of FGF/Wnt signalling interactions in modulating fasted associated regeneration. It opens up further questions as to why this occurs, how this is beneficial to adapting to a fasting state, and the potential for translation.

  2. Reviewer #1 (Public Review):

    The authors provide a comprehensive series of experiments to show that IF promotes rapid hepatocyte proliferation driven by the dual action of systemic FGF15 (intetinally-derived) and localized WNT signaling. Hepatocyte proliferation during periods of IF maintains a steady liver-to-body-mass ratio. This study provides the first example of the dietary influence on adult hepatocyte proliferation and is highly relevant to the putative beneficial effects of IF in multiple chronic diseases. Additionally, it challenges the view that liver tissue is quiescent except in patholgical injury.

  3. Reviewer #2 (Public Review):

    The authors set out to study whether there is altered liver regeneration under physiological homeostatic conditions depending on whether an experimental model is offered continuous feeding or intermittently fasted. They report, using a series of murine models in male mice, that hepatic adjustments to fasting/refeeding occur including hyperproliferation of pericentral hepatocytes during a period of relative liver enlargement. It is interesting to note that this occurs 1 week after daily fasting/feeding cycles and appears to occur very quickly following the reintroduction of food. During fasting, they show that the liver shrinks relative to body weight then, as demonstrated by a series of lineage tracing experiments, undergoes relative hyperproliferation, particularly by pericentral hepatocytes. This was shown using an Axin2-based reporter and additionally through zonal analysis or a confetti-multicolored reporter used to trace individual clones. This response appears stable then for upto 3 months. Ideally, additional data showing the liver and body weight individually would help to give an impression of whether the predominant effect is due to changes in body weight or liver weight but it appears implicit that there is an active contraction of liver and hepatocyte size and number during fasting. This is then followed by rapid growth upon refeeding, presumably without major changes in body weight.

    It is not clear whether the length of fasting is critical and what the proliferative and metabolic state of the liver is immediately prior to refeeding. It is also unclear whether the relative expansion of pericentral hepatocytes results in an expansion of the pericentral zone or whether these hepatocytes then repopulate other zonal compartments of the liver. They do provide single-cell transcriptomic data which supports the expansion of pericentral transcripts, however, whether this represents a functionally advantageous liver metabolism and how this is achieved remains will be important questions for the future. The link changes to bile acids to altered expression of Cyp7A1, which suggests a role for altered bile acid metabolism in the fasting state. It would be interesting, in the future, to explore whether a liver-to-intestinal feedback loop exists utilising the altered hepatic bile acids occurring during fasting/refeeding to signal back to the intestine for example. This would also then potentially have implications for liver disease states including cholestatic liver diseases.

    Mechanistically the authors use hepatocyte-targeted FGF receptor depletion (Klb) or Wnt/b-catenin transcription factor depletion (Tbx3), through efficient adeno-associated viral vector targeting to manipulate these axes combined with hepatocellular FGF overexpression. They demonstrate that the FGF receptor Klb is expressed throughout the lobule and that its global knockout results in the loss of the pericentral proliferative response in fasting/refeeding. It is interesting to note that with the loss of Klb particularly a senescence response occurs in the areas that previously underwent proliferation in response to IF. Similarly, the loss of Klb alters the metabolic rewiring which occurred during the IF response, unlike Tbx3 depletion. Tbx depletion was separately shown to result in a polyploidisation response within the normally diploid pericentral area, consistent with the previous report from this group.

    Broadly the authors achieve their aim of both describing the effects resulting from fasting upon liver regenerative biology and also shedding significant insights mechanistically into this process. Overall, these results are highly provocative and raise important questions when interpreting murine studies. These include whether the experimental effect on liver pathophysiology might be explained by or influenced by altered dietary intake as a result of animal husbandry or animal pathology. It will also be interesting in the future what effect broader dietary modifications have on the liver, and other organs, physiologically. These would include but are not limited to a high-fat diet, altered microbiome, variable fasting, and background body habitus. It also has implications for what happens in response to fasting/refeeding during development and the longer-term adaptive responses to this.