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.
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
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