CD248 expression in human adipose tissue is upregulated in obesity and following glucocorticoid exposure: a mediator of insulin resistance and adipose dysfunction?

Abstract Background CD248 is a transmembrane glycoprotein implicated in fibrosis, hypoxia, and insulin resistance, but its role in human adipose tissue remains incompletely understood. Because glucocorticoids regulate these processes, we investigated whether CD248 is glucocorticoid responsive and characterized its expression across adipose depots and sexes in obesity. Methods CD248 expression was assessed in adipose tissue obtained by needle biopsy (75 male/114 female, BMI: 20.1–47.9 kg/m 2 ) and surgical sampling (24 male/39 female, BMI: 20.0–54.4 kg/m 2 ) from individuals without type 2 diabetes, and in an additional cohort with type 2 diabetes (21 male/33 female, BMI: 22.4–42.4 kg/m 2 ). Adipose tissue, isolated adipocytes and stromal vascular fraction were exposed to cortisol and dexamethasone. Circulating CD248 was analyzed in 44,545 participants from the UK Biobank Pharma Proteomics Project. Results CD248 expression was higher in subcutaneous adipose tissue in obesity at mRNA (86%) and protein (2-fold) levels, with BMI as the strongest independent predictor. Expression did not differ between individuals with and without type 2 diabetes. Depot-specific differences were identified, with lower CD248 expression in omental adipose tissue than subcutaneous adipose tissue and opposing BMI associations. Sex-specific differences were observed at the protein level, with higher CD248 abundance in females with obesity. Transcriptomic analysis identified remodelling-related pathways in subcutaneous adipose tissue and metabolic pathways in omental adipose tissue. Dexamethasone and cortisol increased CD248 gene expression, and dexamethasone increased CD248 unglycosylated protein in adipocytes. Circulating CD248 increased with BMI and was higher in females with obesity, mirroring adipose tissue protein. Conclusion Our findings identify CD248 as a glucocorticoid-responsive and depot-specific marker associated with adiposity and metabolic disturbances, suggesting a potential role in obesity-related adipose tissue dysfunction.