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.

越来越多的证据支持 p53 肿瘤抑制因子在代谢中的重要性，但 p53 介导的代谢控制机制仍然知之甚少。在这里，我们将多功能 E4F1 蛋白鉴定为脂肪细胞中 p53 代谢功能的关键调节因子。虽然 E4F1 表达在肥胖期间上调，但 E4f1在小鼠脂肪组织中的失活导致与胰岛素抵抗和防止诱导肥胖相关的瘦表型。缺乏 E4F1 的脂肪细胞会激活参与脂质代谢的 p53 依赖性转录程序。E4F1 和 p53 之间的直接相互作用及其对硬脂酰辅酶 A 去饱和酶 1的共同募集位点在调节脂肪细胞中单不饱和脂肪酸的合成中起重要作用。与这种 E4F1-p53-硬脂酰辅酶 A 去饱和酶 1轴在脂肪细胞中的作用一致，p53失活或与油酸盐的饮食互补部分恢复了 E4F1 缺陷小鼠的肥胖并改善了胰岛素敏感性。总之，我们的研究结果确定了 E4F1 和 p53 在控制与肥胖和胰岛素抵抗相关的脂肪细胞脂质代谢方面的串扰。