Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice

  1. Georges Raad
  2. Fabrizio Serra
  3. Luc Martin
  4. Marie-Alix Derieppe
  5. Jérôme Gilleron
  6. Vera L Costa
  7. Didier F Pisani
  8. Ez-Zoubir Amri
  9. Michele Trabucchi
  10. Valerie Grandjean  Is a corresponding author
  1. Université Côte d'Azur, CNRS, Inserm, France
  2. Inserm, France
  3. French Institute of Health and Medical Research, France

Abstract

Obesity is a growing societal scourge. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal western diet feeding for five consecutive generations in mice induces an enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational western-diet-fed males develop a 'healthy' overweight phenotype characterized by normal glucose metabolism and without fatty liver that persists for 4 subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE138989 and GSE148972. All data generated or analyses during this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Georges Raad

    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:" 0000-0001-8800-2796
  2. Fabrizio Serra

    C3M, Inserm, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Luc Martin

    iBV, Université Côte d'Azur, CNRS, Inserm, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Marie-Alix Derieppe

    iBV, Université Côte d'Azur, CNRS, Inserm, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Jérôme Gilleron

    U1065, French Institute of Health and Medical Research, NICE, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Vera L Costa

    C3M, Inserm, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Didier F Pisani

    iBV, Université Côte d'Azur, CNRS, Inserm, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Ez-Zoubir Amri

    iBV, Université Côte d'Azur, CNRS, Inserm, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Michele Trabucchi

    C3M, Inserm, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Valerie Grandjean

    C3M, Inserm, Nice, France
    For correspondence
    grandjea@unice.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1661-7411

Funding

Agence Nationale de la Recherche (NR-12-ADAPT-0022)

  • Georges Raad

Fonds Francais pour l'Alimentation et la Sante (15D52)

  • Marie-Alix Derieppe

UCA-IDEX

  • Fabrizio Serra

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. David E James, The University of Sydney, Australia

Ethics

Animal experimentation: All mouse experiments were conducted in accordance with the French and European legislations for the care and use of research animals. All of the animals were handled according to approved institutional animal care and use committee (APAFIS#8729-2017012716401597 (V7)) protocols (#381) of the Ministère de l'Enseignement Supérieur de la Recherche et de l'innovation. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Nice (Permit Number: 217-36).

Version history

  1. Received: August 3, 2020
  2. Accepted: March 28, 2021
  3. Accepted Manuscript published: March 30, 2021 (version 1)
  4. Version of Record published: April 16, 2021 (version 2)
  5. Version of Record updated: April 20, 2021 (version 3)

Copyright

© 2021, Raad 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. Georges Raad
  2. Fabrizio Serra
  3. Luc Martin
  4. Marie-Alix Derieppe
  5. Jérôme Gilleron
  6. Vera L Costa
  7. Didier F Pisani
  8. Ez-Zoubir Amri
  9. Michele Trabucchi
  10. Valerie Grandjean
(2021)
Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice
eLife 10:e61736.
https://doi.org/10.7554/eLife.61736

Share this article

https://doi.org/10.7554/eLife.61736

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