Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1.
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..
Skurk
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Else Kröner-Fresenius-Centre for Nutritional Medicine, Technical University of Munich, Freising-Weihenstephan, Germany.
Hauner
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D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000097:blood; D005342:Fibrinolysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D024821:Metabolic Syndrome / Q000097:blood; D009765:Obesity / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000378:metabolism; D012306:Risk
D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1