The Role of p53 in Adipocyte Differentiation and Lipid Metabolism in Obese Mice via Transcriptional Regulation of Lgals3.

Abstract

This study investigates the regulatory role of p53 on Lgals3 expression and its impact on preadipocyte differentiation, fatty acid synthesis, and oxidation in obesity. Bioinformatics analysis of six obesity-related microarray datasets and single-cell RNA sequencing (scRNA-seq) data identified Lgals3 as a key obesity-associated gene. A high-fat diet (HF) mouse model was established to evaluate obesity-related phenotypes, including body weight, hepatic Lgals3 expression, adipose tissue pathology, blood lipid profiles, and glucose tolerance. In vitro experiments using 3T3-L1 cells were conducted to assess adipocyte differentiation, fatty acid synthase (FAS) activity, and glucose uptake. The interaction between p53 and the Lgals3 promoter was analyzed via dual-luciferase reporter and chromatin immunoprecipitation assays. Key metabolic genes and proteins were quantified by RT-qPCR and Western blot. HF mice exhibited significant weight gain, elevated Lgals3 expression, and altered lipid profiles. In vitro, p53 was shown to transcriptionally repress Lgals3, thereby reducing adipocyte differentiation, FAS activity, and glucose uptake. In vivo, p53 overexpression led to downregulation of Lgals3 and improvement in obesity-related metabolic outcomes, whereas Lgals3 overexpression counteracted these effects. p53 inhibits Lgals3 expression, suppressing adipocyte differentiation and improving obesity-related metabolic dysfunction, highlighting its potential as a therapeutic target in obesity management.