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

Sarkar, Abby; Jin, Yinhua; DeFelice, Brian C.; Logan, Cheryl A.; Yang, Yan; Anbarchian, Teni; Wu, Peng; Morri, Maurizio; Neff, Norma; Nguyen, Huy; Rulifson, Eric; Fish, Matthew; Kaye, Avi Gurion; Jaimes, Azalia M Martínez; Nusse, Roel

doi:10.7554/elife.82311

Cited by 17 publications

(11 citation statements)

References 42 publications

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“…Moreover, the pericentral hepatocytes temporally acquire a more periportal hepatocyte phenotype, at least at the level of gene expression. Sarkar et al have reported that intermittent fasting interacts with WNT signaling, which is consistent with our findings 56 . Previous studies have demonstrated that the WNT signaling gradient is established at the time of weaning and is a necessary regulator of hepatocyte lobule zonation 57,58, 59 .…”

Section: Discussionsupporting

confidence: 94%

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states

Okada,

Landgraf,

Xiaoli

et al. 2024

Preprint

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The liver acts as a master regulator of metabolic homeostasis in part by performing gluconeogenesis. This process is dysregulated in type 2 diabetes, leading to elevated hepatic glucose output. The parenchymal cells of the liver (hepatocytes) are heterogeneous, existing on an axis between the portal triad and the central vein, and perform distinct functions depending on location in the lobule. Here, using single cell analysis of hepatocytes across the liver lobule, we demonstrate that gluconeogenic gene expression (Pck1 and G6pc) is relatively low in the fed state and gradually increases first in the periportal hepatocytes during the initial fasting period. As the time of fasting progresses, pericentral hepatocyte gluconeogenic gene expression increases, and following entry into the starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression to the periportal hepatocytes. Similarly, pyruvate-dependent gluconeogenic activity is approximately 10-fold higher in the periportal hepatocytes during the initial fasting state but only 1.5-fold higher in the starvation state. In parallel, starvation suppresses canonical beta-catenin signaling and modulates expression of pericentral and periportal glutamine synthetase and glutaminase, resulting in an enhanced pericentral glutamine-dependent gluconeogenesis. These findings demonstrate that hepatocyte gluconeogenic gene expression and gluconeogenic activity are highly spatially and temporally plastic across the liver lobule, underscoring the critical importance of using well-defined feeding and fasting conditions to define the basis of hepatic insulin resistance and glucose production.

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Section: Discussionsupporting

confidence: 94%

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states

Okada,

Landgraf,

Xiaoli

et al. 2024

Preprint

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show abstract

“…We also observed robust structural changes in the livers of IF mice (Fig 1K and Appendix Fig S1B), where hepatocytes showed an oedematous morphology. This hepatocyte oedema resembled the one reported upon 1‐week of IF as a compensatory mechanism to fluctuating liver size between the fasting and fed states (preprint: Sarkar et al , 2021). Our data show that liver remodelling persists after 3 months of IF.…”

Section: Resultssupporting

confidence: 77%

Adult neural stem cells and neurogenesis are resilient to intermittent fasting

Gabarró‐Solanas,

Davaatseren,

Kleifeld

et al. 2023

EMBO Reports

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Intermittent fasting (IF) is a promising strategy to counteract ageing shown to increase the number of adult‐born neurons in the dentate gyrus of mice. However, it is unclear which steps of the adult neurogenesis process are regulated by IF. The number of adult neural stem cells (NSCs) decreases with age in an activation‐dependent manner and, to counteract this loss, adult NSCs are found in a quiescent state which ensures their long‐term maintenance. We aimed to determine if and how IF affects adult NSCs in the hippocampus. To identify the effects of every‐other‐day IF on NSCs and all following steps in the neurogenic lineage, we combined fasting with lineage tracing and label retention assays. We show here that IF does not affect NSC activation or maintenance and, that contrary to previous reports, IF does not increase neurogenesis. The same results are obtained regardless of strain, sex, diet length, tamoxifen administration or new‐born neuron identification method. Our data suggest that NSCs maintain homeostasis upon IF and that this intervention is not a reliable strategy to increase adult neurogenesis.

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“…A previous study in Rosa26-Cas9 knock-in mouse showed that constitutive SpCas9 expression did not result in any detectable toxicity or morphological abnormalities in multiple organs (including the brain, kidney, liver, spleen, and heart tissue) of this transgenic strain [ 24 ]. Multiple studies have provided evidence of the safety of Cas9 mice by showcasing the utilization of diverse tissues and cells from these murine models [ 34 , 35 , 36 ]. However, long-term SpCas9 expression and its associated toxicity have not been characterized in ocular tissues in these mice, which can be bred for germline transmission of the Cas9 allele.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Evaluation of Retinal Morphology and Function in Rosa26-Cas9 Knock-In Mice

Mohan

Dubey

Jung

et al. 2023

IJMS

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The CRISPR/Cas9 system is a robust, efficient, and cost-effective gene editing tool widely adopted in translational studies of ocular diseases. However, in vivo CRISPR-based editing in animal models poses challenges such as the efficient delivery of the CRISPR components in viral vectors with limited packaging capacity and a Cas9-associated immune response. Using a germline Cas9-expressing mouse model would help to overcome these limitations. Here, we evaluated the long-term effects of SpCas9 expression on retinal morphology and function using Rosa26-Cas9 knock-in mice. We observed abundant SpCas9 expression in the RPE and retina of Rosa26-Cas9 mice using the real-time polymerase chain reaction (RT-PCR), Western blotting, and immunostaining. SD-OCT imaging and histological analysis of the RPE, retinal layers, and vasculature showed no apparent structural abnormalities in adult and aged Cas9 mice. Full-field electroretinogram of adult and aged Cas9 mice showed no long-term functional changes in the retinal tissues because of constitutive Cas9 expression. The current study showed that both the retina and RPE maintain their phenotypic and functional features in Cas9 knock-in mice, establishing this as an ideal animal model for developing therapeutics for retinal diseases.

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

Cited by 17 publications

References 42 publications

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states

Adult neural stem cells and neurogenesis are resilient to intermittent fasting

Long-Term Evaluation of Retinal Morphology and Function in Rosa26-Cas9 Knock-In Mice

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