ARHGEF3 coordinates adipocyte hypertrophy and differentiation through dual YAP-RhoA and PPARγ activation

Introduction Obesity presents a significant global health burden, necessitating insights into the molecular drivers of adipogenesis and adipose tissue regulation. Objectives This study investigates the role of Rho guanine nucleotide exchange factor 3 (ARHGEF3) in adipocyte differentiation and hypertrophy, focusing on its influence on adipogenesis and body weight regulation under high-fat diet conditions. Methods ARHGEF3^−/− mice and littermate controls were subjected to a high-fat diet (HFD) and underwent comprehensive metabolic phenotyping. In vitro studies in C3H10T1/2 cells were conducted to assess ARHGEF3′s role in adipogenesis, utilizing quantitative PCR, western blotting, chromatin immunoprecipitation (ChIP), immunoprecipitation (IP), immunostaining, and luciferase reporter assays. Results ARHGEF3 expression increased in white adipose tissue (WAT) of HFD-fed mice and during adipogenic differentiation in C3H10T1/2 cells. ARHGEF3-deficient mice exhibited reduced weight gain and adipocyte size, correlating with decreased RhoA expression and altered cytoskeletal dynamics. Additionally, ARHGEF3 facilitated yes-associated protein (YAP) nuclear translocation and its direct binding to the RhoA promoter, an effect reliant on ARHGEF3. ARHGEF3 also enhanced the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ), establishing a reciprocal activation loop to drive adipocyte differentiation and hypertrophy. Conclusion ARHGEF3 emerges as a pivotal regulator of adipocyte dynamics by coordinating YAP-RhoA signaling and enhancing PPARγ activity. These findings offer novel therapeutic insights for addressing obesity and related metabolic disorders.