Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of tissue-type plasminogen activator and has an important role in regulating the fibrinolytic system and thrombus formation. Higher plasma PAI-1 concentrations impair fibrinolysis, which could account for its predictability for cardiovascular events [1,2]. Obesity, an independent risk factor for cardiovascular diseases is associated with increased plasma PAI-1 values [3,4].The mechanisms involved in increased PAI-1 production in obesity have not been fully explained. The insulin-resistance syndrome, a cluster of metabolic abnormalities, accompanying visceral types of obesity could be an important regulator of PAI-1 expression. Indeed, all the variables related to the insulin resistance syndrome (insulinaemia, BMI, waistto-hip ratio (WHR), serum triglyceride and HDL cholesterol concentration) are strongly related to Diabetologia (2001 Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss Abstract Aims/hypothesis. Abdominal fat produces plasminogen activator inhibitor-1 (PAI-1) and could contribute to increased plasma PAI-1 values in human obesity associated with insulin resistance. Femoral fat, which is not associated with insulin resistance, is thought to be metabolically different from the abdominal fat. This study aimed to assess PAI-1 expression in these two fat territories in obese and lean subjects and to determine if concomitant changes of plasma and adipose tissue PAI-1 values occur after weight reduction.Methods. In 24 obese and 16 lean subjects, PAI-1 expression in abdominal and femoral subcutaneous fat, plasma PAI-1, insulin, triglyceride concentrations and insulin resistance were determined at the start of the study and in obese subjects after a 3-month weight reduction programme as well.Results. PAI-1 mRNA content in the abdominal subcutaneous fat was higher in obese than in lean subjects and positively correlated with plasma PAI-1 values (p < 0.01) and markers of insulin resistance (p < 0.05). In 18 obese subjects, re-examined after successful dieting, PAI-1 mRNA content decreased in the abdominal subcutaneous fat along with plasma PAI-1. However, the absolute changes of these two variables were not associated. In contrast, PAI-1 mRNA content in the femoral subcutaneous fat did not differ between lean and obese subjects, was not associated with plasma PAI-1 values or with markers of insulin resistance, and did not change after weight loss. Conclusion/interpretation. Only the abdominal, but not the femoral subcutaneous fat PAI-1 expression is a potential contributor to increases in plasma PAI-1 in obesity. Both plasma and abdominal subcutaneous fat PAI-1 values decreased significantly after weight reduction, although their absolute changes were not associated. [Diabetologia (2001

Improved fibrinolysis by an intensive lifestyle intervention in subjects with impaired glucose tolerance. The Finnish Diabetes Prevention Study

“…Our 1-year results are in accordance with those previously obtained in a Swedish study [20]. In connection with the weight decline, our subjects' insulin sensitivity improved, which may partly explain the reduction in PAI-1 [30]. Surprisingly, there is one lifestyle intervention study in which marked weight loss and a decrease in insulin resistance were not accompanied by any decrease in PAI-1 [21].…”

“…The decline of PAI-1 has been shown to be more closely related to changes in adipose tissue than to changes in insulin levels [31]. Several studies have shown decreased PAI-1 levels after weight loss [17,18,[30][31][32], and the decrease seems to depend on the magnitude of the weight loss [17]. Furthermore, the PAI-1 level has been shown to increase when weight is regained [31].…”

Can inactivators of plasminogen activator inhibitor alleviate the burden of obesity and diabetes? (Review)

“…It has also been found that PAI-1 activity/ antigen in plasma are positively and moderately associated with BMI. Moreover weight reduction substantially reduces plasma PAI-1 in obese people (47,48). It has been shown that inhibitors of PAI-1 reduce dietary fat-induced obesity in C57BL/6 mice.…”

Identification and modulation of a caveolae-dependent signal pathway that regulates plasminogen activator inhibitor-1 in insulin-resistant adipocytes

“…We also explore the pharmacological disruption of the E2F-pRB interaction to release free E2F, which we hypothesize will attenuate PAI-1 transcription and hence its plasma level. Adipocytes are chosen for this study, because they are responsible for obesity, abundant in caveolae (20), highly sensitive to insulin (Ͼ200,000 receptors per cell) (21), the primary site for insulin resistance (22), and a major contributor of plasma PAI-1 in the obese (23).…”