Missing evidence of alternative c-Cbl activation in human fat cells

Aim: Obesity is a major risk factor for developing insulin resistance. Hypertrophy of adipocytes is considered to be a significant predictor of this situation. Previous studies have shown that besides the classical IRS/AKT-pathway the alternative activation of CAP/cbl might be responsible for glucose uptake, at least in rodent cell lines. However, no data are available taking cell size into account. This study was therefore designed to measure insulin driven signalling in small and hypertrophied adipocytes.

Materials and methods: Isolated subcutaneous adipocytes were obtained from healthy subjects undergoing elective abdominal surgery. Cells were fractionated into small and large fat cells. Glucose uptake in mature adipocytes was measured using radio-labelled ³H-glucose. Insulin sensitivity was assessed by both basal and insulin stimulated protein levels of p-IRS/IRS-1, p-Akt/Akt, and p-c-Cbl/c-Cbl.

Results: Insulin stimulated glucose uptake was completely abolished in hypertrophic adipocytes. Although total amounts IRS-1, Akt/PKB, and c-Cbl were comparable between small and hypertrophied fat cells, insulin significantly activated IRS-1 and Akt/PKB only in small adipocytes. However, c-Cbl was detectable only in trace amounts and did not show significant activation upon insulin treatment.

Conclusions: Adipocyte hypertrophy caused impairment of insulin signalling and consequently of glucose uptake. A significant evidence for alternative insulin signal via c-Cbl signal transduction could not be established. Therefore we conclude that glucose uptake is predominantly mediated through IRS-1/Akt/PKB in human adipocytes.