Obesity and impaired fibrinolysis: role of adipose
production of plasminogen activator inhibitor-1
T Skurk1and H Hauner1*
1Else Kro ¨ner-Fresenius-Centre for Nutritional Medicine, Technical University of Munich, Freising-Weihenstephan, Germany
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-a and transforming growth factor-b, 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.
International Journal of Obesity (2004) 28, 1357–1364. doi:10.1038/sj.ijo.0802778
Published online 31 August 2004
Keywords: adipose tissue; cardiovascular disease; fibrinolysis; plasminogen activator inhibitor-1; visceral fat
Obesity is the most common nutritional disorder in the
industrialized world. Approximately 60% of the adult
population in these countries is overweight or obese.1This
epidemic of excess body fat mass has far-reaching con-
sequences as it is considered to be the most potent
modifiable promoter of the metabolic syndrome which is
characterized by the common occurrence of abdominal fat
distribution, elevated blood pressure, lipid disturbances, and
glucose intolerance. In an expanded definition, Reaven also
allocated impaired fibrinolysis to the syndrome based on
clinical data that suggest a close relationship between
elevated plasma concentrations of plasminogen activator
inhibitor-1 (PAI-1) and variables of the metabolic syndrome
including insulin resistance.2
There is now growing evidence that patients with features
of the metabolic syndrome carry an elevated risk of
developing cardiovascular disease.3,4Other prospective stu-
dies have shown that a reduced fibrinolytic capacity, for
example, caused by elevated PAI-1 activity, independently
predicts cardiovascular events in young men after myocar-
dial infarction,5as well as in men and women with angina
pectoris.6Elevated plasma PAI-1 was also reported to be an
independent predictor for sudden death in patients with
Fibrinolysis can be described as a cascade of enzymatic
reactions that results in the degradation of fibrin and is
determined by a variety of PAs and inhibitors. Among the
inhibitory factors, the rapid acting PAI-1 is the most
important inhibitor of plasma fibrinolytic activity. PAI-1 is
a glycoprotein that is composed of 379 amino acids and has
an apparent molecular weight of 48kDa. PAI-1 is a member
of the superfamily of serine-protease inhibitors (serpins) and
serves as a pseudosubstrate for PA. The main production sites
Received 15 September 2003; revised 9 January 2004; accepted 2
February 2004; published online 31 August 2004
*Correspondence: Dr H Hauner, Else Kro ¨ner-Fresenius-Centre for Nutri-
tional Medicine, Technical University of Munich, Hochfeldweg 1, D-85350
International Journal of Obesity (2004) 28, 1357–1364
& 2004 Nature Publishing Group All rights reserved 0307-0565/04 $30.00
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Obesity and impaired fibrinolysis
T Skurk and H Hauner
International Journal of Obesity