COL6A3 Expression in Adipocytes Associates with Insulin Resistance and Depends on PPARγ and Adipocyte Size

ObjectiveCOL6A3 may modulate adipose tissue function in obesity and insulin resistance. A role for human adipocytes linking COL6A3 with insulin resistance warrants exploration. MethodsCOL6A3 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 mol kg(-1) min(-1), respectively) (1), or by HOMA-IR and TG/HDL ratio (2). ResultsWhole 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). ConclusionIncreased adipocyte COL6A3 expression associates with insulin resistance in humans, which may involve impaired PPAR-mediated adipocyte development.