Elevated Expression of Transforming Growth Factor-β in Adipose Tissue from Obese Mice

Samad, Fahumiya; Yamamoto, Kōji; Pandey, Manjula; Loskutoff, David J.

doi:10.1007/bf03401666

Cited by 278 publications

(253 citation statements)

References 53 publications

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“…We have been able to extend these initial observations considerably by studying genetically obese (ob/ob) mice. 9,10,19 Plasma PAI-1 activity was approximately fivefold higher in these mice than in their lean counterparts, and this elevation increased further as a function of age. 10 Importantly, PAI-1 gene expression was significantly elevated in the epididymal, subcutaneous, and brown adipose tissues of obese mice compared with the lean controls.…”

Section: Selected Abbreviations and Acronymsmentioning

confidence: 88%

“…TGF-␤ did not induce PAI-1 mRNA expression in large-vessel endothelial cells in adipose tissue (Fig 1E), in agreement with previous studies in the kidney. 3 TGF-␤ also stimulated PAI-1 gene expression by cultured mouse 19,21 and human 22 adipocytes. Interestingly, the level of TGF-␤ mRNA was significantly higher in the adipose tissue of both ob/ob and db/db mice when compared with their lean counterparts, 19 and this increase again was due to increased expression of TGF-␤ mRNA by mature adipocytes and stroma/vascular cells.…”

Section: Tgf-␤mentioning

confidence: 92%

“…The multifunctional cytokine TGF-␤ stimulates PAI-1 biosynthesis by a large variety of cultured cells, 3 and infusion of TGF-␤ into rabbits 30 and mice 15,19 dramatically increased plasma PAI-1 activity and induced PAI-1 mRNA in numerous tissues. In the mouse, the most TGF-␤-responsive tissue in terms of PAI-1 appeared to be adipose tissue (References 15 and 19; Figs 1 and 2, compare panels A and E).…”

Section: Tgf-␤mentioning

confidence: 99%

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The Adipocyte and Hemostatic Balance in Obesity

Loskutoff

Samad

1998

ATVB

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261

159

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P lasminogen activator inhibitor 1 is the primary physiological inhibitor of plasminogen activation in vivo, and elevations in plasma PAI-1 appear to compromise normal fibrin clearance mechanisms and promote thrombosis. PAI-1 is dramatically upregulated in obesity, a complex condition associated with increased risk for myocardial infarction, accelerated atherosclerosis, hypertension, glucose intolerance, insulin resistance, hyperinsulinemia, and NIDDM. In spite of the apparent link between elevated PAI-1 levels and thrombotic disease, little is known about the origin of this plasma inhibitor in obesity/NIDDM or about the signals that control its biosynthesis. Potential insights into the underlying molecular events have come from recent studies of genetically obese mice and of cultured adipocytes. These studies are reviewed here.* They emphasize the key role played by the adipocyte, a cell whose numbers, size, and metabolic activity are grossly altered in obesity/NIDDM. They also suggest that multiple cytokines, hormones, and growth factors may be involved, and they raise the possibility that the abnormal expression of other hemostatic genes by adipocytes in obesity/NIDDM may also contribute to the cardiovascular complications of this disorder. In this regard, our preliminary studies indicate that TF gene expression is elevated in the adipose tissues of the obese mouse. Properties of PAI-1PAI-1 appears to be the primary physiological inhibitor of plasminogen activation in blood, since it is the only PAI found complexed with single-chain tissue-type PA in carefully collected human plasma, and the second-order rate constant for its interaction with tissue-type PA and urokinase-type PA (Ϸ3.5ϫ10 7 [mol/L] Ϫ1 ⅐ s Ϫ1 ) is at least two orders of magnitude higher than that of other PAIs. [1][2][3][4] The normal concentration of PAI-1 protein in human plasma ranges from 6 to 80 ng/mL with a geometric mean at 24 ng/mL, whereas that of tissuetype PA is 5 to 10 ng/mL. Abnormalities in the concentration of PAI-1 are frequently associated with vascular disease. For example, the inhibitor is elevated in a variety of thrombotic conditions, including myocardial infarction and deep venous thrombosis. Elevated PAI-1 also correlates with thrombosis in animal models, and transgenic mice that overexpress PAI-1 have been reported to develop venous thrombosis. 5 On the other hand, the absence of PAI-1 in humans leads to life-long bleeding problems presumably resulting from the development of a hyperfibrinolytic state, and disruption of the PAI-1 gene in mice is also associated with a mild hyperfibrinolytic state as manifested by increased resistance to endotoxin-induced thrombosis. 5 Finally, neutralizing plasma PAI-1 activity with specific antibodies or by the use of PAI-1 inhibitors 4,6 enhances spontaneous or tissue-type PA-mediated thrombolysis. These observations emphasize that imbalances in the PA/PAI-1 ratio are likely to promote either thrombosis or bleeding. As summarized in the next section, this balance is severely disturbed ...

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Section: Selected Abbreviations and Acronymsmentioning

confidence: 88%

Section: Tgf-␤mentioning

confidence: 92%

Section: Tgf-␤mentioning

confidence: 99%

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The Adipocyte and Hemostatic Balance in Obesity

Loskutoff

Samad

1998

ATVB

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261

159

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“…TGF- mRNA levels are increased in both the mature adipocyte and the stromal/vascular cell fractions of the adipose tissues from obese mice. The augmented expression of TGF- in the obese adipose tissue may increase adipocyte precursor cell proliferation, thereby contributing to the excessive cellularity of the fat depots associated with the obese phenotype (Samad et al, 1997). TNF- is a multipotential cytokine with several immunological functions.…”

Section: Growth Factors and Cytokinesmentioning

confidence: 99%

Angiogenesis and development of adipose tissue

Christiaens

Lijnen

2010

Molecular and Cellular Endocrinology

193

159

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“…Furthermore, it has been reported as an important factor in the adipocyte-and macrophage-driven inflammation in the adipose tissue, and that could mediate the elevation of PAI-1, promoting a prothrombotic state [41]. Also, TSP-1 has been described as a major regulator of the transforming growth factor (TGF)-β activity [11,31], which, together with the increased 3 PAI-1 levels, are correlated with different features of obesity, insulin-resistance, and metabolic syndrome [1,29,37]. Finally, it has been described higher TSP-1 gene expression in visceral respect to subcutaneous adipose tissue in obese subjects [35].…”

Section: Introductionmentioning

confidence: 99%

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

et al. 2011

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Thrombospondin 1 (TSP-1), an anti-angiogenic factor and TGF-β activity regulator, has been recently recognized as an adipokine that correlates with obesity, inflammation and insulin-resistance processes. In the present study, epididymal adipocytes of rats that were fed a chow (C) or a high fat diet (HFD) for 50 days, were isolated and incubated (24-72 h) in low (LG; 5.6 mM) or high (HG; 25 mM) glucose, in presence or absence of 1.6 nM insulin. Rats fed the HF diet showed an established obesity state. Serum TSP-1 levels and TSP-1 mRNA basal expression of adipocytes from HFD rats were higher than those from controls. Adipocytes from HFD animals presented an insulin-resistance state, as suggested by the lower insulin-stimulated glucose uptake as compared to controls. TSP-1 expression in culture was higher in adipocytes from obese animals at 24 h, but when the adipocytes were treated with HG, these expression levels dropped dramatically. Later at 72 h, TSP-1 expression was lower in adipocytes from HFD rats, and no effects of the other treatments were observed. Surprisingly, the secretion levels of this protein at 72 h were increased significantly by the HG treatment in both types of adipocytes, although they were even higher in adipocytes from obese animals. Finally, cell viability was significantly reduced by HG treatment in both types of adipocytes. In summary, TSP-1 expression/secretion was modulated in an in vitro model of insulinresistant adipocytes. The difference between expression and secretion patterns suggests a post-transcriptional regulation. The present study confirms that TPS-1 is closely associated with obesity-related mechanisms.

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Elevated Expression of Transforming Growth Factor-β in Adipose Tissue from Obese Mice

Abstract: TNF-alpha contributes to the elevated TGF-beta expression demonstrated in the adipose tissue of obese mice. A potential role for TGF-beta in the increased PAI-1 and vascular pathologies associated with obesity/NIDDM is suggested.

Cited by 278 publications

References 53 publications

The Adipocyte and Hemostatic Balance in Obesity

The Adipocyte and Hemostatic Balance in Obesity

Angiogenesis and development of adipose tissue

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

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