Nat Commun.: co-auth.: L.Fajas

Nat Commun. 2021 Dec 2;12(1):7037. doi: 10.1038/s41467-021-27307-3.

The multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes

Matthieu Lacroix # 1 2Laetitia K Linares # 1 2Natalia Rueda-Rincon 3Katarzyna Bloch 3Michela Di Michele 1 2Carlo De Blasio 1 2Caroline Fau 1 2Laurie Gayte 1 2Emilie Blanchet 1Aline Mairal 4Rita Derua 5Fernando Cardona 6Diane Beuzelin 4Jean-Sebastien Annicotte 7Nelly Pirot 1 8Adeline Torro 1Francisco J Tinahones 9Florence Bernex 1 8Justine Bertrand-Michel 4Dominique Langin 4 10Lluis Fajas 11Johannes V Swinnen 3Laurent Le Cam 12 13


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.