KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism
- Université Côte d'Azur, France
- Université Côte d'Azur, CNRS, Inserm, France
- Mayo Clinic, United States
Abstract
The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Krüppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver. Here, we show that the loss of the clock-controlled KLF10 in hepatocytes results in extensive reprogramming of the mouse liver circadian transcriptome, which in turn, alters the temporal coordination of pathways associated with energy metabolism. We also show that glucose and fructose induce Klf10, which helps mitigate glucose intolerance and hepatic steatosis in mice challenged with a sugar beverage. Functional genomics further reveal that KLF10 target genes are primarily involved in central carbon metabolism. Together, these findings show that in the liver, KLF10 integrates circadian timing and sugar metabolism related signaling, and serves as a transcriptional brake that protects against the deleterious effects of increased sugar consumption.
Data availability
Sequencing data have been deposited in European Nucleotide Archive under accession codes PRJEB39035, 696 PRJEB39036, PRJEB40195.All data generated or annalysed during this study are included in the manuscript and supplemental files. Source data files have been provided for figures 1-7.
Article and author information
Author details
Funding
Agence Nationale de la Recherche (ANR-15-CE14-0016-01)
- Franck Delaunay
- Michèle Teboul
Agence Nationale de la Recherche (ANR-18-CE14-0019-02)
- Franck Delaunay
- Michèle Teboul
Agence Nationale de la Recherche (ANR-11-LABX-0028-01)
- Anthony A Ruberto
- Franck Delaunay
- Michèle Teboul
Agence Nationale de la Recherche (ANR-15-IDEX-01)
- Franck Delaunay
- Michèle Teboul
Canceropole Provence Cote d'Azur (MetaboCell)
- Mohamed Mehiri
Universite Cote d'Azur (ATER)
- Johana S Revel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal studies were approved by the local committee for animal ethics Comité Institutionnel d'Éthique Pour l'Animal de Laboratoire (CIEPAL-Azur; Authorized protocols: PEA 244 and 557) and conducted in accordance with the CNRS and INSERM institutional guidelines.
Reviewing Editor
- Peter Tontonoz, University of California, Los Angeles, United States
Version history
- Received: December 8, 2020
- Preprint posted: December 23, 2020 (view preprint)
- Accepted: August 15, 2021
- Accepted Manuscript published: August 17, 2021 (version 1)
- Version of Record published: September 1, 2021 (version 2)
Copyright
© 2021, Ruberto et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism
eLife 10:e65574.
https://doi.org/10.7554/eLife.65574
Further reading
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The MRTF–SRF pathway has been extensively studied for its crucial role in driving the expression of a large number of genes involved in actin cytoskeleton of various cell types. However, the specific contribution of MRTF–SRF in hair cells remains unknown. In this study, we showed that hair cell-specific deletion of Srf or Mrtfb, but not Mrtfa, leads to similar defects in the development of stereocilia dimensions and the maintenance of cuticular plate integrity. We used fluorescence-activated cell sorting-based hair cell RNA-Seq analysis to investigate the mechanistic underpinnings of the changes observed in Srf and Mrtfb mutants, respectively. Interestingly, the transcriptome analysis revealed distinct profiles of genes regulated by Srf and Mrtfb, suggesting different transcriptional regulation mechanisms of actin cytoskeleton activities mediated by Srf and Mrtfb. Exogenous delivery of calponin 2 using Adeno-associated virus transduction in Srf mutants partially rescued the impairments of stereocilia dimensions and the F-actin intensity of cuticular plate, suggesting the involvement of Cnn2, as an Srf downstream target, in regulating the hair bundle morphology and cuticular plate actin cytoskeleton organization. Our study uncovers, for the first time, the unexpected differential transcriptional regulation of actin cytoskeleton mediated by Srf and Mrtfb in hair cells, and also demonstrates the critical role of SRF–CNN2 in modulating actin dynamics of the stereocilia and cuticular plate, providing new insights into the molecular mechanism underlying hair cell development and maintenance.
