TNF-α, but not IL-6, stimulates plasminogen activator inhibitor-1 expression in human subcutaneous adipose tissue

2005 ◽  
Vol 98 (6) ◽  
pp. 2019-2023 ◽  
Author(s):  
Peter Plomgaard ◽  
Pernille Keller ◽  
Charlotte Keller ◽  
Bente Klarlund Pedersen
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Plasminogen Activator ◽  
Subcutaneous Adipose Tissue ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Subcutaneous Adipose ◽  
Activator Inhibitor ◽  
Pai 1

Plasminogen activator inhibitor-1 (PAI-1) is produced by adipose tissue, and elevated PAI-1 levels in plasma are a risk factor in the metabolic syndrome. We investigated the regulatory effects of TNF-α and IL-6 on PAI-1 gene induction in human adipose tissue. Twenty healthy men underwent a 3-h infusion of either recombinant human TNF-α ( n = 8), recombinant human IL-6 ( n = 6), or vehicle ( n = 6). Biopsies were obtained from the subcutaneous abdominal adipose tissue at preinfusion, at 1, 2, and 3 h during the infusion, and at 2 h after the infusion. The mRNA expression of PAI-1 in the adipose tissue was measured using real-time PCR. The plasma levels of TNF-α and IL-6 reached 18 and 99 pg/ml, respectively, during the infusions. During the TNF-α infusion, adipose PAI-1 mRNA expression increased 2.5-fold at 1 h, 6-fold at 2 h, 9-fold at 3 h, and declined to 2-fold 2 h after the infusion stopped but did not change during IL-6 infusion and vehicle. These data demonstrate that TNF-α rather than IL-6 stimulates an increase in PAI-1 mRNA in the subcutaneous adipose tissue, suggesting that TNF-α may be involved in the pathogenesis of related metabolic disorders.

Regional Variation in Plasminogen Activator Inhibitor-1 Expression in Adipose Tissue from Obese Individuals

2000 ◽  
Vol 83 (04) ◽  
pp. 545-548 ◽  
Author(s):  
Vanessa Van Harmelen ◽  
Johan Hoffstedt ◽  
Per Lundquist ◽  
Hubert Vidal ◽  
Veronika Stemme ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Subcutaneous Adipose Tissue ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Visceral Adipose ◽  
Subcutaneous Adipose ◽  
Activator Inhibitor ◽  
Pai 1

SummaryHigh plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity and adipose tissue has recently been suggested to be a source of circulating PAI-1 in humans. In the present study, differences in adipose tissue gene expression and protein secretion rate of PAI-1 between subcutaneous and visceral adipose tissue was analysed in specimens obtained from 22 obese individuals. The secretion rate of PAI-1 was two-fold higher in subcutaneous adipose tissue than in visceral adipose tissue (292 ± 50 vs 138 ± 24 ng PAI-1/107 cells, P <0.05). In accordance with the secretion data, subcutaneous adipose tissue contained about three-fold higher levels of PAI-1 mRNA than visceral adipose tissue (2.43 ± 0.37 vs 0.81 ± 0.12 attomole PAI-1 mRNA/µg total RNA, P <0.001). PAI-1 secretion from subcutaneous but not from visceral adipose tissue correlated significantly with cell size (r = 0.43, P <0.05). In summary, subcutaneous adipose tissue secreted greater amounts of PAI-1 and had a higher PAI-1 gene expression than visceral adipose tissue from the same obese individuals. Bearing in mind that subcutaneous adipose tissue is the largest fat depot these finding may be important for the coagulation abnormalities associated with obesity.

Role of Gender and Genetic Variance in Plasminogen Activator Inhibitor-1 Secretion from Human Adipose Tissue

2000 ◽  
Vol 83 (02) ◽  
pp. 304-308 ◽  
Author(s):  
Hans Wahrenberg ◽  
Per Eriksson ◽  
Peter Arner ◽  
Vanessa Van Harmelen
Keyword(s):  
Body Mass Index ◽  
Adipose Tissue ◽  
Gender Difference ◽  
Subcutaneous Adipose Tissue ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Plasma Triglycerides ◽  
Subcutaneous Adipose ◽  
Activator Inhibitor ◽  
Pai 1

SummaryGender and the 4G/5G polymorphism in the plasminogen activator inhibitor 1 (PAI-1) gene are believed to play a role in the regulation of plasma PAI-1 activity. Adipose tissue has been found to be an important source of PAI-1. The possible influence of gender and the 4G/5G polymorphism in the PAI-1 gene on PAI-1 secretion from abdominal subcutaneous adipose tissue was investigated in 59 women and 32 men. The subjects were apparantly healthy, although they differed markedly inter-individually in body mass index (21-53 kg/m2). The 4G/5G polymorphism did not influence the adipose secretion rate of PAI-1 or plasma PAI-1 activity. There was no gender difference in the adipose secretion of PAI-1. In multiple regression, including body mass index (BMI), waist-to-hip ratio (WHR), plasma insulin and plasma triglycerides as the independent and adipose PAI-1 secretion as the dependent variable, only BMI and plasma triglycerides correlated independently with adipose PAI-1 secretion (r = 0.54, p <0.05; r = 0.51, p <0.05, respectively). Men had a two times higher plasma PAI-1 activity than women (p <0.05). This gender difference was mainly due to gender differences in WHR. In multiple regression analysis, BMI and WHR were identified to be independently correlated with plasma PAI-1 activity (r = 0.60, p <0.05; r = 0.52, p = 0.01, respectively). In conclusion, neither gender nor the 4G/5G polymorphism in the PAI-1 gene are associated with secretion of PAI-1 from abdominal subcutaneous adipose tissue.

scholarly journals Plasminogen Activator Inhibitor-1 is Regulated Through Dietary Fat Intake and Heritability: Studies in Twins

2017 ◽  
Vol 20 (4) ◽  
pp. 338-348 ◽  
Author(s):  
Anna Janina Engstler ◽  
Turid Frahnow ◽  
Michael Kruse ◽  
Andreas Friedrich Hermann Pfeiffer ◽  
Ina Bergheim
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Plasminogen Activator ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Fatty Tissue ◽  
Plasminogen Activator Inhibitor 1 ◽  
The Impact ◽  
Activator Inhibitor ◽  
Pai 1

In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI-1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18–70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p< .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients — for example, a switch to a fat-rich diet — affects PAI-1 concentrations in humans and that this is highly heritable.

Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-α?

1999 ◽  
Vol 143 (1) ◽  
pp. 81-90 ◽  
Author(s):  
M. Cigolini ◽  
M. Tonoli ◽  
L. Borgato ◽  
L. Frigotto ◽  
F. Manzato ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Human Adipose Tissue ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Activator Inhibitor

Developmental Expression of Plasminogen Activator Inhibitor-1 Associated With Thrombopoietin-Dependent Megakaryocytic Differentiation

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 475-482 ◽  
Author(s):  
Seiji Madoiwa ◽  
Norio Komatsu ◽  
Jun Mimuro ◽  
Kouzoh Kimura ◽  
Michio Matsuda ◽  
...  
Keyword(s):  
Cord Blood ◽  
Mrna Expression ◽  
Progenitor Cells ◽  
Plasminogen Activator ◽  
Messenger Rna ◽  
Plasminogen Activator Inhibitor ◽  
Developmental Expression ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Plasminogen activator inhibitor-1 (PAI-1) is present in the platelet -granule and is released on activation. However, there is some debate as to whether the megakaryocyte and platelet synthesize PAI-1, take it up from plasma, or both. We examined the expression of PAI-1 in differentiating megakaryocytic progenitor cells (UT-7) and in CD34+/CD41− cells from cord blood. UT-7 cells differentiated with thrombopoietin (TPO) resembled megakaryocytes (UT-7/TPO) with respect to morphology, ploidy, and the expression of glycoprotein IIb-IIIa. PAI-1 messenger RNA (mRNA) expression was upregulated and PAI-1 protein synthesized in the UT-7/TPO cells accumulated in the cytoplasm without being released spontaneously. In contrast, erythropoietin (EPO)-stimulated UT-7 cells (UT-7/EPO) did not express PAI-1 mRNA after stimulation with TPO because they do not have endogenous c-Mpl. After cotransfection with human wild-typec-mpl, the cells (UT-7/EPO-MPL) responded to phorbol 12-myristate 13-acetate (PMA), tumor necrosis factor- (TNF-), and interleukin-1β (IL-1β) with enhanced PAI-1 mRNA expression within 24 to 48 hours. However, induction of PAI-1 mRNA in UT-7/EPO-MPL cells by TPO required at least 14-days stimulation. UT-7/EPO cells expressing c-Mpl changed their morphology and the other characteristics similar to the UT-7/TPO cells. TPO also differentiated human cord blood CD34+/CD41− cells to CD34−/CD41+ cells, generated morphologically mature megakaryocytes, and induced the expression of PAI-1 mRNA. These results suggest that both PAI-1 mRNA and de novo PAI-1 protein synthesis is induced after differentiation of immature progenitor cells into megakaryocytes by TPO.

Plasminogen activator inhibitor-1 modulates adipocyte differentiation

2006 ◽  
Vol 290 (1) ◽  
pp. E103-E113 ◽  
Author(s):  
Xiubin Liang ◽  
Talerngsak Kanjanabuch ◽  
Su-Li Mao ◽  
Chuan-Ming Hao ◽  
Yi-Wei Tang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mrna Expression ◽  
Glucose Uptake ◽  
Plasminogen Activator ◽  
Adipocyte Differentiation ◽  
Plasminogen Activator Inhibitor ◽  
Plasmin Activity ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Increased plasminogen activator inhibitor-1 (PAI-1) is linked to obesity and insulin resistance. However, the functional role of PAI-1 in adipocytes is unknown. This study was designed to investigate effects and underlying mechanisms of PAI-1 on glucose uptake in adipocytes and on adipocyte differentiation. Using primary cultured adipocytes from PAI-1+/+ and PAI-1−/− mice, we found that PAI-1 deficiency promoted adipocyte differentiation, enhanced basal and insulin-stimulated glucose uptake, and protected against tumor necrosis factor-α-induced adipocyte dedifferentiation and insulin resistance. These beneficial effects were associated with upregulated glucose transporter 4 at basal and insulin-stimulated states and upregulated peroxisome proliferator-activated receptor-γ (PPARγ) and adiponectin along with downregulated resistin mRNA in differentiated PAI-1−/− vs. PAI-1+/+ adipocytes. Similarly, inhibition of PAI-1 with a neutralizing anti-PAI-1 antibody in differentiated 3T3-L1 adipocytes further promoted adipocyte differentiation and glucose uptake, which was associated with increased expression of transcription factors PPARγ, CCAAT enhancer-binding protein-α (C/EBPα), and the adipocyte-selective fatty acid-binding protein aP2, thus mimicking the phenotype in PAI-1−/− primary adipocytes. Conversely, overexpression of PAI-1 by adenovirus-mediated gene transfer in 3T3-L1 adipocytes inhibited differentiation and reduced PPARγ, C/EBPα, and aP2 expression. This was also associated with a decrease in urokinase-type plasminogen activator mRNA expression, decreased plasmin activity, and increased collagen I mRNA expression. Collectively, these results indicate that absence or inhibition of PAI-1 in adipocytes protects against insulin resistance by promoting glucose uptake and adipocyte differentiation via increased PPARγ expression. We postulate that these PAI-1 effects on adipocytes may, at least in part, be mediated via modulation of plasmin activity and extracellular matrix components.

TNF-α and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes

1999 ◽  
Vol 276 (6) ◽  
pp. C1391-C1397 ◽  
Author(s):  
Tomohiro Sakamoto ◽  
Janet Woodcock-Mitchell ◽  
Kousuke Marutsuka ◽  
John J. Mitchell ◽  
Burton E. Sobel ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Synergistic Effects ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activators ◽  
System Capacity ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Factor Α ◽  
Activator Inhibitor ◽  
Pai 1

Obesity is associated with hyperinsulinemia and elevated concentrations of tumor necrosis factor-α (TNF-α) in adipose tissue. TNF-α has been implicated as an inducer of the synthesis of plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of fibrinolysis, mediated by plasminogen activators in cultured adipocytes. To identify mechanism(s) through which TNF-α induces PAI-1, 3T3-L1 preadipocytes were differentiated into adipocytes and exposed to TNF-α for 24 h. TNF-α selectively increased the synthesis of PAI-1 without increasing activity of plasminogen activators. Both superoxide (generated by xanthine oxidase plus hypoxanthine) and hydrogen peroxide were potent inducers of PAI-1, and hydroxyl radical scavengers completely abolished the TNF-α induction of PAI-1. Exposure of adipocytes to TNF-α or insulin alone over 5 days increased PAI-1 production. These agonists exert synergistic effects. Results obtained suggest that TNF-α stimulates PAI-1 production by adipocytes, an effect potentiated by insulin, and that adipocyte generation of reactive oxygen centered radicals mediates the induction of PAI-1 production by TNF-α. Because induction of PAI-1 by TNF-α is potentiated synergistically by insulin, both agonists appear likely to contribute to the impairment of fibrinolytic system capacity typical in obese, hyperinsulinemic patients.

Impairment of adipose tissue development by hypoxia is not mediated by plasminogen activator inhibitor-1

2006 ◽  
Vol 95 (01) ◽  
pp. 174-181 ◽  
Author(s):  
Fabrizio Semeraro ◽  
Gabor Voros ◽  
Désiré Collen ◽  
H. Lijnen
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Development ◽  
Plasminogen Activator Inhibitor 1 ◽  
Adipose Tissue Development ◽  
Activator Inhibitor ◽  
Pai 1

SummaryHypoxia in rodents and humans is associated with a reduction of body fat on the one hand, and with enhanced expression of plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of the fibrinolytic system, on the other hand. It was the objective of this study to investigate whether impairment of adipose tissue development by hypoxia may be mediated by PAI-1. Five week old male wild-type (WT) C57Bl/6 mice were fed a standard (SFD) or high fat (HFD) diet and kept under normoxic or hypoxic (10% O2) conditions. In addition, PAI-1 deficient mice and WT littermates were kept on HFD under normoxia or hypoxia. In vitro, the effect of hypoxia (2% O2) was investigated on differentiation of 3T3-L1 cells into adipocytes. Hypoxia induced a significant reduction of weight gain in WT mice on either SFD or HFD, accompanied by lower weights of subcutaneous (SC) and gonadal (GON) fat. Under hypoxic conditions, adipocytes in the adipose tissues were significantly smaller, whereas blood vessel size and density were larger. Serum PAI-1 levels were enhanced in hypoxic mice on SFD but not on HFD, and overall did not correlate with the observed changes in adipose tissue composition. Furthermore, the effects of hypoxia on adipose tissue in mice on HFD were not affected by deficiency of PAI-1. The inhibiting effect of hypoxia on in vitro preadipocyte differentiation was not mediated by PAI-1 activity. In conclusion, impairment of in vivo adipose tissue development and in vitro differentiation of preadipocytes by hypoxia is not mediated by PAI-1.

Sign in / Sign up

Export Citation Format

Share Document