Reduced fibrinolytic response in obese children: Association with high baseline activity of the fast acting plasminogen activator inhibitor (PAI-1)

Proc. Natl. Acad. Sci. U.S.A.

Uysal

Wiesbrock

et al. 1999

213

155

Obesity is associated with a cluster of abnormalities, including hypertension, insulin resistance, hyperinsulinemia, and elevated levels of both plasminogen activator inhibitor 1 (PAI-1) and transforming growth factor ␤ (TGF-␤). Although these changes may increase the risk for accelerated atherosclerosis and fatal myocardial infarction, the underlying molecular mechanisms remain to be defined. Although tumor necrosis factor ␣ (TNF-␣) has been implicated in the insulin resistance associated with obesity, its role in other disorders of obesity is largely unknown. In this report, we show that in obese (ob͞ob) mice, neutralization of TNF-␣ or deletion of both TNF receptors (TNFRs) results in significantly reduced levels of plasma PAI-1 antigen, plasma insulin, and adipose tissue PAI-1 and TGF-␤ mRNAs. Studies in which exogenous TNF-␣ was infused into lean mice lacking individual TNFRs indicate that TNF-␣ signaling of PAI-1 in adipose tissue can be mediated by either the p55 or the p75 TNFR. However, TNF-␣ signaling of TGF-␤ mRNA expression in adipose tissue is mediated exclusively via the p55 TNFR. Our results suggest that TNF-␣ is a common link between the insulin resistance and elevated PAI-1 and TGF-␤ in obesity. The chronic elevation of TNF-␣ in obesity thus may directly promote the development of the complex cardiovascular risk profile associated with this condition.

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

See 1 more Smart Citation

Tumor necrosis factor α is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1

Proc. Natl. Acad. Sci. U.S.A.

Uysal

Wiesbrock

et al. 1999

213

155

“…Obesity is an independent risk factor for the development of atherosclerosis and cardiovascular disease (1,2) and is associated with related metabolic disorders such as hypertriglyceridemia, hyperinsulinemia, and non-insulin-dependent diabetes (2,3). Interestingly, in a limited number of clinical studies, significant correlations have been established between elevated plasminogen activator inhibitor-I (PAI-1) levels and obesity (4)(5)(6)(7), and this abnormal expression of PAI-1 has mRNA in the epididymal fat pad (13). In obese animals, the mass of the epididymal fat pad typically increases several-fold, primarily because of an increase in the size and number of adipocytes.…”

Section: Introductionmentioning

confidence: 99%

Tissue Distribution and Regulation of Plasminogen Activator Inhibitor-1 in Obese Mice

Loskutoff

1996

Mol Med

193

198

“…Plasma plasminogen activator inhibitor 1 (PAI-1) is also elevated in human obesity (23)(24)(25)(26), and we have made considerable progress in understanding the tissue and cellular origin of this increase by studying genetically obese (ob͞ob) mice. The ob͞ob mice cannot produce leptin (27), and as a consequence are associated with early onset obesity and severe insulin resistance (28).…”

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confidence: 99%

Tissue factor gene expression in the adipose tissues of obese mice

Proc. Natl. Acad. Sci. U.S.A.

Pandey

Loskutoff

1998

126

Altered expression of proteins of the fibrinolytic and coagulation cascades in obesity may contribute to the cardiovascular risk associated with this condition. We previously reported that plasminogen activator inhibitor 1 (PAI-1) is dramatically up-regulated in the plasma and adipose tissues of genetically obese mice. This change may disturb normal hemostatic balance and create a severe hypofibrinolytic state. Here we show that tissue factor (TF) gene expression also is significantly elevated in the epididymal and subcutaneous fat pads from ob͞ob mice compared with their lean counterparts, and that its level of expression in obese mice increases with age and the degree of obesity. Cell fractionation and in situ hybridization analysis of adipose tissues indicate that TF mRNA is increased in adipocytes and in unidentified stromal vascular cells. Transforming growth factor ␤ (TGF-␤) is known to be elevated in the adipose tissue of obese mice, and administration of TGF-␤ increased TF mRNA expression in adipocytes in vivo and in vitro. These observations raise the possibility that TF and TGF-␤ may contribute to the increased cardiovascular disease that accompanies obesity and related non-insulin-dependent diabetes mellitus, and that the adipocyte plays a key role in this process. The recent demonstration that TF also inf luences angiogenesis, cell adhesion, and signaling suggests that its exact role in adipose tissue physiology͞pathology, may be complex.