Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue

Plasminogen activator inhibitor 1 (PAI-1) is likely to play a role in vascu lar disease, primarily in subjects with android obesity. It has been demons trated that PAI-1 is overexpressed in adipose tissue from obese subjects an d that visceral adipose tissue produced more PAI-1 than subcutaneous fat. I n the present study the effect of insulin and glucocorticoids, which are ke y mediators of adipose tissue metabolism, was examined in relation to PAI-1 synthesis by human adipose tissue explants (HAT), collagenase isolated hum an adipocytes (IHA), cultured human stromal cells (cSC), and differentiated adipocytes from the murine clonal cell line 3T3-F442A, A significant incre ase in PAI-1 antigen release (1.5-fold) from HAT was detectable after 16 h of treatment with insulin concentrations of at least 10(-8) mol/l, This was associated with a PAI-1 mRNA increase. Concomitant addition of insulin (10 (-8) mol/l) to forskolin (5 x 10(-5) mol/l) reversed the decrease in PAI-1 antigen caused by forskolin alone. No effect on PAI-1 antigen was observed when insulin was incubated with IHA or cSC, 3T3 F442A cells were sensitive to insulin with a four- and twofold increase in PAI-1 antigen and mRNA leve ls, respectively, after 16 h of stimulation, with 10(-8) mol/l, Dexamethaso ne (DXM) significantly enhanced PAI-1 antigen and mRNA expression by HAT (1 .5- and 2.5-fold increase, respectively) at concentrations of at least 10(- 8) mol/l, A higher stimulation was observed with IHA (sevenfold increase) a nd with the differentiated 3T3 F442 cell line. Cortisol was found to be les s potent than DXM, No effect was observed when glucocorticoids were incubat ed with cSC, Coincubation of HAT with insulin (10(-7) mol/l) and DXM (10(-7 ) mol/l) led to an additive effect on PAI-1 synthesis. These results suppor t the hypothesis that PAI-1 expression in human adipose tissue is controlle d by insulin and glucocorticoids and mag help to explain the increase in pl asma PAI-1 levels observed in patients with android obesity.