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. Th e 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 t he GR, in vitro and in vivo. In addition to LPL activity, glucose tole rance, blood pressure and plasma lipids, all variables influenced by c ortisol, were studied in order to evaluate the peripheral antiglucocor ticoid activity of RU 486 in vivo, in man. Addition of both cortisol a nd RU 486 to incubations of human adipose tissue pieces significantly inhibited the increase in LPL activity that could be induced by cortis ol alone (p<0.01). In a ten-fold molarity excess RU 486 totally abolis hed cortisol action (p<0.01). With cortisol and RU 486 in equimolar co ncentrations the RU 486 blockade was probably incomplete and LPL activ ity 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 d ays to healthy men caused a significant rise in serum cortisol levels measured at 0800 hours (p<0.05). The mean LPL activity in the subcutan eous abdominal adipose tissue remained unchanged. The mean level of se rum triglycerides decreased significantly (p<0.01) and there was a neg ative correlation between change in LPL activity and change in triglyc eride levels (r=-0.73, p<0.05). Glucose tolerance and blood pressure w ere not affected, In conclusion, a total blockade of the GR with RU 48 6 can be achieved in human adipose tissue in vitro. The blockade aboli shes the stimulating effect of cortisol on LPL activity suggesting tha t the stimulation is GR dependent. In vivo, with the dose used, the ne gative pituitary feedback regulation probably compensates for the bloc kade, at least during the morning hours, thus obviating any peripheral effect of blockade of the GR.