Blockade of the Glucocorticoid Receptor with RU 486: Effects In Vitro and In Vivo on Human Adipose Tissue Lipoprotein Lipase Activity

Cortisol is known to induce lipoprotein lipase (LPL) activity in human adipose tissue in vitro and in vivo such as in Cushing's syndrome. The significance of the glucocorticoid receptor (GR) for this induction was evaluated in the present study. The synthetic steroid molecule RU 486, a potent glucocorticoid antagonist, was used as a tool to block the GR, in vitro and in vivo. In addition to LPL activity, glucose tolerance, blood pressure and plasma lipids, all variables influenced by Cortisol, were studied in order to evaluate the peripheral antiglucocorticoid activity of RU 486 in vivo, in man. Addition of both Cortisol and RU 486 to incubations of human adipose tissue pieces significantly inhibited the increase in LPL activity that could be induced by Cortisol alone (p<0.01). In a ten-fold molarity excess RU 486 totally abolished Cortisol action (p<0.01). With Cortisol and RU 486 in equimolar concentrations the RU 486 blockade was probably incomplete and LPL activity induced (p<0.05). The results imply that the stimulating effect of Cortisol on LPL activity in human adipose tissue is mediated via the GR. Administration of 400 mg RU 486 at 2200 hours on two consecutive days to healthy men caused a significant rise in serum Cortisol levels measured at 0800 hours (p<0.05). The mean LPL activity in the subcutaneous abdominal adipose tissue remained unchanged. The mean level of serum triglycerides decreased significantly (p<0.01) and there was a negative correlation between change in LPL activity and change in triglyceride levels (r=-0.73, p<0.05). Glucose tolerance and blood pressure were not affected. In conclusion, a total blockade of the GR with RU 486 can be achieved in human adipose tissue in vitro. The blockade abolishes the stimulating effect of Cortisol on LPL activity suggesting that the stimulation is GR dependent. In vivo, with the dose used, the negative pituitary feedback regulation probably compensates for the blockade, at least during the morning hours, thus obviating any peripheral effect of blockade of the GR.