DISTRIBUTION AND REGULATION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN MURINE ADIPOSE-TISSUE IN-VIVO - INDUCTION BY TUMOR-NECROSIS-FACTOR-ALPHA AND LIPOPOLYSACCHARIDE

Although elevated plasma plasminogen activator inhibitor 1 (PAI-1) is associated with obesity, very little is known about its tissue or cell ular origin, or about the events that lead to increased PAI-1 levels u nder obese conditions. Since TNF-alpha is increased in rodents both du ring obesity and in response to endotoxin treatment, we examined the e ffects of these agents on PAI-1 gene expression in the adipose tissue of CB6 mice, In untreated mice, PAI-1 mRNA was detected in both mature adipocytes and in stromal vascular cells. Both TNF-alpha and endotoxi n significantly increased PAI-1 mRNA in the adipose tissue, peaking at 3-8 h. In situ hybridization analysis of adipose tissue from untreate d mice revealed a weak signal for PAI-1 mRNA only in the smooth muscle cells within the vascular wall, In contrast, after endotoxin or TNF-a lpha treatment, PAI-1 mRNA also was detected in adipocytes and in adve ntitial cells of vessels. Endotoxin also induced PAI-1 in endothelial cells, while TNF-alpha. additionally induced it in smooth muscle cells . Mature 3T3-L1 adipocytes in culture also expressed PAI-1 mRNA, and i ts rate of synthesis was also upregulated by TNF-alpha. These studies suggest that the adipose tissue itself may be an important contributor to the elevated PAI-1 levels observed in the plasma under obese condi tions.