Inès Mucel p53 regulates macrophages phenotype and their capacity to handle lipids
Year: 2022
Type: conference-paper
Abstract: Metabolic reprogramming of adipose tissue macrophages (ATM) during obesity plays a major role in adipocytes dysfunction and contributes to the development of insulin resistance (IR) and Type 2 Diabetes. Transcription factors (TF) are crucial regulators of transcriptional programs involved in the polarization and adaptation of macrophages to their environment. Preliminary data showed an increase in the expression and activation of p53 in obese ATM. Thus, we decided to investigate the role of p53 in macrophages polarization, and its impact on adipocyte function. We used bone marrow-derived macrophages (BMDM) knockout (KO) for p53 and control BMDM, that we polarized into macrophages metabolically activated (MMe) with insulin, palmitate, and glucose, which phenocopy obese ATM phenotype. We showed that macrophages polarized into MMe produced inflammatory mediators and expressed lipid handling genes. The invalidation of p53 potentiate the polarization into MMe with an upregulation of genes involved in lipid metabolism such as Pparγ1, Cd36 and Abca1. Moreover, the cellular respiration was increased in p53 KO MMe compared to control MMe, suggesting a better oxidative capacity. In contrast, the activation of p53 before the polarization into MMe decreased the respiration compared to control MMe. Strikingly, compared to conditioned-media (CM) from control MMe, CM from p53 KO MMe did not alter insulin-induced PKB phosphorylation and the expression of insulin signalling genes in adipocytes. Moreover, adipocytes treated with CM from p53 KO MMe exhibited an upregulation of genes involved in lipogenesis. In conclusion, our data suggest that activation of p53 in ATMs during obesity inhibits their ability to manage lipid and their oxidative capacity and contributes to the secretion of factors impairing insulin signalling in adipocytes. Thus, the dysregulation of p53 in macrophages during obesity could contribute to adipose tissue dysfunction and IR.
Source: HAL
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7120630773