Introduction and Objective: Adipocytes expand remarkably in size during positive energy balance, closely linked to metabolic health. However, the molecular mechanisms underlying adipocyte hypertrophy remain poorly understood. This study aims to identify transcriptional drivers of adipocyte hypertrophy in obesity.Methods: Bioinformatics analyses of ChIP-seq on adipocytes under varying nutrient availability identify super-enhancers and their associated transcriptional drivers involved in obesity-induced adipocyte remodeling in vivo. Functional studies in cultured adipocytes, including loss- and gain-of-function experiments, validate these drivers. Adipocyte-specific KO mice are studied to assess changes in adipose tissue remodeling, energy metabolism and glucose homeostasis. Bulk and single-nucleus RNA-seq further elucidate the underlying mechanisms.Results: Serum Response Factor (SRF) is identified as a key transcriptional driver of actin cytoskeletal remodeling, associated with super-enhancers in adipocytes during obesity. In vitro, SRF is both necessary and sufficient for the expression of actin cytoskeletal genes in adipocytes. Adipocyte-specific SRF KO mice exhibit reduced expression of these genes, disrupted actin filament networks and smaller adipocyte size after high-fat diet feeding. Despite similar body weights, these mice develop exacerbated insulin resistance and ectopic lipid accumulation in the liver and brown adipose tissue, attributed to compromised adipocyte cellular integrity and lipid storage. Single-nucleus RNA-seq reveals defective communication between adipocytes and stromal cells, resulting in disrupted vascularization and increased inflammation.Conclusion: SRF plays a crucial role in supporting healthy adipose tissue expansion during obesity by regulating actin cytoskeletal remodeling and facilitating the interactions between adipocytes and stromal cells.
J. So: None. J. Wann: None. K. Kim: None. S. Taleb: None. A. Banks: Research Support; Eli Lilly and Company. Consultant; Keros Therapeutics. E. Rosen: Consultant; Foghorn Therapeutics. Advisory Panel; Source Bio. X. Dong: None. H. Roh: None.
American Diabetes Association (7-21-JDF-056)
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