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-alpha and
transforming growth factor-beta, whereas
catecholamines reduce
PAI-1 production. Interestingly, pharmacological agents such as
thiazolidinediones,
metformin and AT(1)-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..