COL6A3 expression in adipocytes associates with insulin resistance and depends on PPARγ and adipocyte size

Abstract

Objective: COL6A3 may modulate adipose tissue function in obesity and insulin resistance. A role for human adipocytes linking COL6A3 with insulin resistance warrants exploration. Methods: COL6A3 mRNA in abdominal subcutaneous adipose samples was compared between (1) BMI‐matched obese subjects resistant or sensitive to insulin (surgical whole tissue biopsies, n = 30/group), (2) lean/overweight and obese subjects (isolated adipocytes from collagenase‐treated surgical biopsies, n = 11/group), (3) developing primary human adipocytes with/without knockdown of the insulin‐sensitizing adipogenic gene PPARG (collagenase‐treated lipoaspirate, n = 5), and (4) small and large adipocytes from lean/overweight subjects (collagenase‐treated surgical biopsies or lipoaspirate, n = 10). Insulin resistance and sensitivity were assessed by euglycemic‐hyperinsulinemic clamp (glucose infusion rate <60 and >70 μmol kg −1 min −1 , respectively) (1), or by HOMA‐IR and TG/HDL ratio (2). Results: Whole tissue COL6A3 mRNA was 2.6‐fold higher in insulin resistant compared to sensitive subjects ( P < 0.001). In isolated adipocytes, COL6A3 mRNA correlated positively with BMI ( P = 0.007), HOMA‐IR ( P = 0.039), and TG/HDL ( P = 0.004). PPARG knockdown in developing adipocytes increased COL6A3 mRNA 1.5‐fold ( P = 0.043). The inverse relationship with adipocyte development was further supported by 2.8‐fold higher COL6A3 mRNA in small compared to large adipocytes ( P = 0.004). Conclusion: Increased adipocyte COL6A3 expression associates with insulin resistance in humans, which may involve impaired PPARγ‐mediated adipocyte development.