LRRFIP1 Inhibits White Adipocyte Differentiation by Suppressing the E2F6/C/EBPα Axis

Background: To investigate the biological functions of the transcription factor LRR binding FLII interacting protein 1 (LRRFIP1) in white adipocyte differentiation (WAD) and elucidate the underlying molecular regulatory mechanisms involved. Methods: Consensus clustering, differential gene expression screening, and intersection analysis were used to identify transcription factors involved in WAD. Adipogenic differentiation experiments were conducted using C3H10T1/2 cells, and a diet-induced obesity model in C57BL/6J mice was established to investigate the function of LRRFIP1 in WAD in vitro and in vivo. Molecular mechanisms were examined through quantitative real-time polymerase chain reaction, Western blotting, luciferase assays, and chromatin immunoprecipitation. Results: Bioinformatics analyses identified LRRFIP1 as a transcription factor associated with WAD. LRRFIP1 expression was downregulated in white adipose tissues from obese patients and in mature white adipocytes. Silencing LRRFIP1 significantly inhibited WAD in C3H10T1/2 cells and reduced differentiation biomarker expression; in contrast, overexpressing LRRFIP1 had the opposite effects. Mechanistically, LRRFIP1 bound to the E2F transcription factor 6 (E2F6) promoter to suppress E2F6 transcription, thereby downregulating a key differentiation regulator, CCAAT enhancer binding protein alpha (C/EBPα). Furthermore, in a diet-induced obesity model, LRRFIP1 could regulate the differentiation and maturation of inguinal white adipose tissue. Conclusion: Our findings reveal that LRRFIP1 plays a crucial inhibitory role in WAD by negatively regulating the E2F6/C/EBPα axis. This discovery not only enriches our understanding of the molecular networks governing WAD but also holds great promise for creating targeted therapies for obesity and associated metabolic conditions.