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.