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The multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes

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  • Matthieu Lacroix

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    Equipe labélisée Ligue Contre le Cancer)

  • Laetitia K. Linares

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    Equipe labélisée Ligue Contre le Cancer)

  • Natalia Rueda-Rincon

    (KU Leuven–University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer)

  • Katarzyna Bloch

    (KU Leuven–University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer)

  • Michela Di Michele

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    Equipe labélisée Ligue Contre le Cancer)

  • Carlo De Blasio

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    Equipe labélisée Ligue Contre le Cancer)

  • Caroline Fau

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    Equipe labélisée Ligue Contre le Cancer)

  • Laurie Gayte

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    Equipe labélisée Ligue Contre le Cancer)

  • Emilie Blanchet

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier)

  • Aline Mairal

    (I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, INSERM, Université Toulouse III – Paul Sabatier (UPS))

  • Rita Derua

    (KU Leuven–University of Leuven, Department of Cellular and Molecular Medicine)

  • Fernando Cardona

    (University of Malaga)

  • Diane Beuzelin

    (I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, INSERM, Université Toulouse III – Paul Sabatier (UPS))

  • Jean-Sebastien Annicotte

    (Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, CNRS, U1283 - UMR 8199 - EGID)

  • Nelly Pirot

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    BioCampus, RHEM, Université de Montpellier, CNRS, INSERM)

  • Adeline Torro

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier)

  • Francisco J. Tinahones

    (CIBER of Physiopathology, Obesity and Nutrition (CIBEROBN), Málaga, Spain; Unidad de Gestion Clinica de Endocrinologia y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Clinico Virgen de la Victoria)

  • Florence Bernex

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    BioCampus, RHEM, Université de Montpellier, CNRS, INSERM)

  • Justine Bertrand-Michel

    (I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, INSERM, Université Toulouse III – Paul Sabatier (UPS))

  • Dominique Langin

    (I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, INSERM, Université Toulouse III – Paul Sabatier (UPS)
    Toulouse University Hospitals, Department of Clinical Biochemistry)

  • Lluis Fajas

    (Center for Integrative Genomics, University of Lausanne)

  • Johannes V. Swinnen

    (KU Leuven–University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer)

  • Laurent Le Cam

    (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
    Equipe labélisée Ligue Contre le Cancer)

Abstract

Growing evidence supports the importance of the p53 tumor suppressor in metabolism but the mechanisms underlying p53-mediated control of metabolism remain poorly understood. Here, we identify the multifunctional E4F1 protein as a key regulator of p53 metabolic functions in adipocytes. While E4F1 expression is upregulated during obesity, E4f1 inactivation in mouse adipose tissue results in a lean phenotype associated with insulin resistance and protection against induced obesity. Adipocytes lacking E4F1 activate a p53-dependent transcriptional program involved in lipid metabolism. The direct interaction between E4F1 and p53 and their co-recruitment to the Steaoryl-CoA Desaturase-1 locus play an important role to regulate monounsaturated fatty acids synthesis in adipocytes. Consistent with the role of this E4F1-p53-Steaoryl-CoA Desaturase-1 axis in adipocytes, p53 inactivation or diet complementation with oleate partly restore adiposity and improve insulin sensitivity in E4F1-deficient mice. Altogether, our findings identify a crosstalk between E4F1 and p53 in the control of lipid metabolism in adipocytes that is relevant to obesity and insulin resistance.

Suggested Citation

  • Matthieu Lacroix & Laetitia K. Linares & Natalia Rueda-Rincon & Katarzyna Bloch & Michela Di Michele & Carlo De Blasio & Caroline Fau & Laurie Gayte & Emilie Blanchet & Aline Mairal & Rita Derua & Fer, 2021. "The multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27307-3
    DOI: 10.1038/s41467-021-27307-3
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    References listed on IDEAS

    as
    1. Peng Jiang & Wenjing Du & Anthony Mancuso & Kathryn E. Wellen & Xiaolu Yang, 2013. "Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence," Nature, Nature, vol. 493(7434), pages 689-693, January.
    2. Ergün Sahin & Simona Colla & Marc Liesa & Javid Moslehi & Florian L. Müller & Mira Guo & Marcus Cooper & Darrell Kotton & Attila J. Fabian & Carl Walkey & Richard S. Maser & Giovanni Tonon & Friedrich, 2011. "Telomere dysfunction induces metabolic and mitochondrial compromise," Nature, Nature, vol. 470(7334), pages 359-365, February.
    3. Ergün Sahin & Simona Colla & Marc Liesa & Javid Moslehi & Florian L. Müller & Mira Guo & Marcus Cooper & Darrell Kotton & Attila J. Fabian & Carl Walkey & Richard S. Maser & Giovanni Tonon & Friedrich, 2011. "Erratum: Telomere dysfunction induces metabolic and mitochondrial compromise," Nature, Nature, vol. 475(7355), pages 254-254, July.
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