Human deep subcutaneous adipose tissue is enriched for inflammatory and tissue remodeling pathways

Subcutaneous superficial adipose tissue (SAT) and deep adipose tissue (DAT) are anatomically separated by the superficial fascia and differ in both function and histological organization. This study presents a comprehensive transcriptomic comparison between SAT and DAT using bulk and single-cell RNA sequencing. Bulk RNA sequencing revealed that DAT is enriched in genes related to inflammation, tissue remodeling, and oxidative stress. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed significant enrichment of inflammatory response, cytokine signaling, and TNF signaling pathways in DAT, indicating a proinflammatory and remodeling-prone environment. Single-ce7ll RNA sequencing identified distinct differences in immune and stromal cell composition. SAT exhibited higher proportions of anti-inflammatory M2 macrophages and CD8/NK cells, whereas DAT showed an increase in oxidative stress-associated Mox macrophages and specific subtypes of fibroblasts and preadipocytes. <i>MT1X</i> and <i>HMOX1</i> expression in FAPs of DAT supports a stress-responsive phenotype, whereas <i>CCN1</i> expression in FAPs of SAT may reflect a role in structural maintenance. In addition, <i>APOE</i> was upregulated in macrophages of DAT, consistent with its known roles in immune modulation and lipid metabolism. These findings highlight cellular and molecular differences between SAT and DAT, suggesting a more active involvement of DAT in inflammation and tissue remodeling.<b>NEW & NOTEWORTHY</b> This study reveals that human deep subcutaneous adipose tissue (DAT) exhibits a distinct proinflammatory and remodeling-prone gene expression profile compared with superficial adipose tissue (SAT). Using both bulk and single-cell RNA sequencing, the researchers identified an increased presence of oxidative stress-associated macrophages and stress-responsive fibroblasts in DAT, suggesting its stronger involvement in systemic inflammation and metabolic dysfunction.