¹Else Kröner-Fresenius-Centre for Nutritional Medicine, Technical University of Munich, Freising-Weihenstephan, Germany

Correspondence: Dr H Hauner, Else Kröner-Fresenius-Centre for Nutritional Medicine, Technical University of Munich, Hochfeldweg 1, D-85350 Freising-Weihenstephan, Germany. E-mail: hauner@wzw.tum.de

Received 15 September 2003; Revised 9 January 2004; Accepted 2 February 2004; Published online 31 August 2004.

Abstract

Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor- and transforming growth factor-, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT₁-receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease.