KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism

  1. Anthony A Ruberto
  2. Aline Gréchez-Cassiau
  3. Sophie Guérin
  4. Luc Martin
  5. Johana S Revel
  6. Mohamed Mehiri
  7. Malayannan Subramaniam
  8. Franck Delaunay
  9. Michèle Teboul  Is a corresponding author
  1. Université Côte d'Azur, France
  2. Université Côte d'Azur, CNRS, Inserm, France
  3. 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.

The following data sets were generated

Article and author information

Author details

  1. Anthony A Ruberto

    Institut de Biologie Valrose, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Aline Gréchez-Cassiau

    Institut de Biologie Valrose, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Sophie Guérin

    Institut de Biologie Valrose, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Luc Martin

    iBV, Université Côte d'Azur, CNRS, Inserm, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5725-3955
  5. Johana S Revel

    Institut de Chimie de Nice, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Mohamed Mehiri

    Institut de Chimie de Nice, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Malayannan Subramaniam

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Franck Delaunay

    Institut de Biologie Valrose, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4927-1701
  9. Michèle Teboul

    Institut de Biologie Valrose, Université Côte d'Azur, Nice, France
    For correspondence
    Michele.Teboul@univ-cotedazur.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3418-4384

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

  1. Peter Tontonoz, University of California, Los Angeles, United States

Publication history

  1. Received: December 8, 2020
  2. Preprint posted: December 23, 2020 (view preprint)
  3. Accepted: August 15, 2021
  4. Accepted Manuscript published: August 17, 2021 (version 1)
  5. 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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  1. Anthony A Ruberto
  2. Aline Gréchez-Cassiau
  3. Sophie Guérin
  4. Luc Martin
  5. Johana S Revel
  6. Mohamed Mehiri
  7. Malayannan Subramaniam
  8. Franck Delaunay
  9. Michèle Teboul
(2021)
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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