Serum Response Factor (SRF) drives actin cytoskeletal organization in adipocytes to support adaptive hypertrophic expansion and tissue remodeling during obesity

Background: Adipocyte hypertrophy, the unique ability of adipocytes to expand in response to positive energy balance, is a key determinant of metabolic health during obesity. However, the molecular mechanisms that govern this adaptive growth are not fully understood. Methods: We performed super-enhancer profiling to identify transcriptional regulators activated in adipocytes under obesogenic conditions. Functional roles of the identified regulator were assessed through in vitro and in vivo analyses, including adipocyte-specific deletion of target gene and subsequent single-nucleus RNA sequencing. Results: Serum Response Factor (SRF) was identified as a pivotal driver of actin cytoskeletal remodeling in adipocytes during obesity. SRF was both necessary and sufficient for the expression of actin cytoskeletal genes in vitro. In vivo, adipocyte-specific SRF deletion reduced actin cytoskeletal gene expression, disrupted filamentous actin networks, and impaired adipocyte enlargement following high-fat diet feeding. Despite similar body weights, mice lacking adipocyte SRF exhibited exacerbated insulin resistance and ectopic lipid accumulation in the liver and brown adipose tissues, reflecting compromised adipocyte integrity and lipid storage capacity. Single-nucleus RNA-seq further revealed that defective actin cytoskeletons in adipocytes disrupted tissue homeostasis, resulting in impaired vascularization and elevated inflammation. Conclusion: These findings establish SRF as a central regulator of actin cytoskeletal organization in adipocytes, essential for supporting healthy hypertrophic expansion and proper tissue remodeling during obesity. SRF emerges as a critical determinant of metabolic health and a potential therapeutic target for obesity-related disorders.