The multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes

Matthieu Lacroix,Johannes V Swinnen,Justine Bertrand‐Michel ,Katarzyna Bloch,Fernando Cardona,Lluís Fajas ,Diane Beuzelin,Carlo De Blasio,Élodie Blanchet ,Nelly Pirot,Dominique Langin,Laurie Gayte,Francisco J Tinahones,Adeline Torro,Michela Di Michele,Jean-Sébastien Annicotte ,Laëtitia K Linares ,Aline Mairal,Rita Derua,Caroline Fau,Natalia Rueda-Rincón ,Florence Bernex,Laurent Le Cam

doi:10.1038/s41467-021-27307-3

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.

Highlights

Growing evidence supports the importance of the p53 tumor suppressor in metabolism but the mechanisms underlying p53-mediated control of metabolism remain poorly understood
We identify a link between the multifunctional E4F1 protein and the p53 tumor suppressor in adipocyte differentiation and lipid metabolism that is essential for normal adipose tissue function
Using several genetically engineered mice lacking E4F1 in adipocytes, we show that E4f1 inactivation induces a p53mediated response implicated in lipid metabolism

Summary

Introduction

Growing evidence supports the importance of the p53 tumor suppressor in metabolism but the mechanisms underlying p53-mediated control of metabolism remain poorly understood. Several reports have highlighted the importance of p53 in lipid metabolism through the direct transcriptional regulation of genes implicated in fatty acid degradation and lipid synthesis[8], including Lipin[1] (Lpin)[9], carnitine O-octanoyltransferase (CROT)[10], carnitine palmitoyltransferase 1C (Cpt1c)[11], Sterol Regulatory Element Binding Protein 1c (Srebp1)[12], Acad1113, and Npc1L114. The multifunctional protein E4F1 controls the balance between proliferation and cell survival through various mechanisms involving the p53 and pRB tumor suppressors[20,21,22], the post-transcriptional stabilization of the cdk inhibitor p21[WAF123, the transcriptional repression of the cyclin A2 promoter[24,25], and the regulation of the DNA-damage response[26,27,28]. We show that E4F1 is a key regulator of p53associated metabolic functions in adipocytes that plays an important role in obesity and insulin sensitivity

Methods

Results

Conclusion