Production of Plasminogen Activator Inhibitor 1 by Human Adipose Tissue: Possible Link Between Visceral Fat Accumulation and Vascular Disease

Abstract

Plasminogen activator inhibitor type 1 (PAI-1) contributes to the pathogenesis of atherothrombosis. Its plasma level is strongly correlated with parameters that define the insulin resistance syndrome, in particular with BMI and visceral accumulation of body fat, suggesting that PAI-1 may be an adipose tissue-derived circulating peptide. The present study was designed to investigate PAI-1 expression by human adipose tissue and its different cellular fractions. Special interest has been paid to the amount of PAI-1 antigen produced by omental versus subcutaneous fat. PAI-1 protein detected by immunolocalization was present at the stromal and adipocyte levels. PAI-1 mRNA was detected in stromal vascular cells freshly isolated and under culture conditions. It was also detected in whole adipose tissue and adipocyte fraction under culture conditions. The mRNA signal from the adipocyte fraction was detected as early as 2 h of incubation. The increase in PAI-1 mRNA was followed by an increase in PAI-1 antigen in the conditioned medium that was suppressed by treatment with cycloheximide. Transforming growth factor-beta1 significantly increased PAI-1 antigen production by the adipocyte fraction, whereas tumor necrosis factor-alpha did not have any effect. Interestingly, after 5 h of incubation, omental tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, whereas similar production of leptin by the two territories was observed. These results strongly suggest that human adipose tissue, in particular visceral tissue, can be an important contributor to the elevated plasma PAI-1 levels observed in central obesity.

Subcutaneous adipose tissue expression of plasminogen activator inhibitor-1 (PAI-1) in nondiabetic and Type 2 diabetic subjects

“…Recently, the expression of PAI-1 protein and mRNA have also been demonstrated in adipose tissue [9,10]. Subcutaneous adipose tissue PAI-1 gene expression and release of PAI-1 protein is increased in obesity [10], and visceral fat produces more PAI-1 protein than subcutaneous fat [9]. The mechanism responsible for enhanced expression of adipose tissue PAI-1 mRNA in obesity [10] is not known.…”

“…The source of circulating PAI-1 protein is not presently clear, but hepatocytes [6,7] and endothelial cells [8] may contribute to elevated plasma PAI-1 levels in insulinresistant states. Recently, the expression of PAI-1 protein and mRNA have also been demonstrated in adipose tissue [9,10]. Subcutaneous adipose tissue PAI-1 gene expression and release of PAI-1 protein is increased in obesity [10], and visceral fat produces more PAI-1 protein than subcutaneous fat [9].…”

Carboxypeptidase E and thrombospondin-1 are differently expressed in subcutaneous and visceral fat of obese subjects

“…Visceral adipocytes are more metabolically active, more sensitive to catecholamine-induced lipolysis and less senby the two fat depots. Examples are leptin [10,11], plasminogen activator inhibitor-1 (PAI-1) [12] and interleukin (IL)-6 [13]. Despite physiological differences between visceral and subcutaneous adipocytes, the molecular basis for these differences is still largely unknown, and identification of genes whose expression is strongly site related may contribute to identifying candidate genes for visceral obesity [14].…”

Obesity and Related Disorders

“…PAI-1 is expressed mainly in endothelial and liver cells and also in adipose tissue (Alessi 1997). PAI-1 is involved in weight gain and insulin resistance (Ma 2004) and markedly upregulated in the conditions of obesity and insulin resistance (Alessi 1997).…”

“…PAI-1 is involved in weight gain and insulin resistance (Ma 2004) and markedly upregulated in the conditions of obesity and insulin resistance (Alessi 1997). Accordingly, disruption of the PAI-1 gene leads to reduced adiposity in ob/ob mice (Ma 2004).…”