Collagen VI-derived endotrophin impairs adipocyte function and insulin action in human obesity

CONTEXT: Obesity-associated adipose tissue dysfunction is characterized by extracellular matrix (ECM) remodeling and fibrosis, where collagen VI and its bioactive cleavage peptide endotrophin have been implicated as key mediators. OBJECTIVE: Characterize collagen VI alpha-3 (COL6A3) depot-specific expression in obesity and determine whether endotrophin impairs adipocyte metabolism and insulin responsiveness. DESIGN, SETTING, AND PARTICIPANTS: COL6A3 expression was examined in paired subcutaneous (SAT) and omental adipose tissue (OAT) from 60 individuals spanning a broad Body-Mass-Index (BMI) range. Plasma endotrophin was measured in a subset of the cohort (n=42). Endotrophin effects were assessed in adipose explants, primary human and SGBS adipocytes. MAIN OUTCOME ME: asures. Depot-specific COL6A3 expression relative to BMI and endotrophin's effects on adipose tissue gene expression, GLUT4 levels, and adipocyte glucose uptake rate. RESULTS: COL6A3 expression was associated with adiposity only in SAT. BMI remained an independent predictor after adjustment for age, sex, and metabolic covariates. COL6A3 co-expression patterns were positively associated with ECM remodeling and inflammation genes in both depots, while inverse associations with lipid metabolism and insulin signaling genes were specific to SAT. Circulating endotrophin levels were associated with fat mass percentage and triglyceride-to-HDL-cholesterol ratio, but not with adipose tissue COL6A3 expression. Endotrophin treatment reduced expression of PPARγ, SLC2A4 (GLUT4), and NR3C1, decreased GLUT4 protein, and impaired adipocyte insulin-stimulated glucose uptake rate without affecting AKT phosphorylation. Endotrophin reduced PPARγ, DGAT2, and SLC2A4 expression in differentiating SGBS adipocytes. Glucocorticoids upregulated COL6A3 in both depots. CONCLUSIONS: These findings implicate COL6A3-associated ECM remodelling and endotrophin in adipose dysfunction and impaired adipocyte insulin responsiveness in obesity.