The multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes

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, Fernando Cardona, Diane Beuzelin, Jean-Sebastien Annicotte, Nelly Pirot, Adeline Torro, Francisco J. Tinahones, Florence Bernex, Justine Bertrand-Michel, Dominique Langin, Lluis Fajas, Johannes V. Swinnen and Laurent Le Cam ()
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Matthieu Lacroix: IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
Laetitia K. Linares: IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
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
Carlo De Blasio: IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
Caroline Fau: IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
Laurie Gayte: IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Univ Montpellier, Institut régional du Cancer de Montpellier
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
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
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)
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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27307-3

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