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 2, Laetitia K Linares # 1 2, Natalia Rueda-Rincon 3, Katarzyna Bloch 3, Michela Di Michele 1 2, Carlo De Blasio 1 2, Caroline Fau 1 2, Laurie Gayte 1 2, Emilie Blanchet 1, Aline Mairal 4, Rita Derua 5, Fernando Cardona 6, Diane Beuzelin 4, Jean-Sebastien Annicotte 7, Nelly Pirot 1 8, Adeline Torro 1, Francisco J Tinahones 9, Florence Bernex 1 8, Justine Bertrand-Michel 4, Dominique Langin 4 10, Lluis Fajas 11, Johannes V Swinnen 3, Laurent Le Cam 12 13
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.
- PMID: 34857760
- DOI: 10.1038/s41467-021-27307-3