Enhanced expression of PAI–1 in visceral fat: Possible contributor to vascular disease in obeisty

Shimomura, Iichiro; Funahashi, Tohru; Takahashi, Masahiko; Maeda, Kazuhisa; Kotani, Kazuaki; Nakamura, Tadashi; Yamashita, Shizuya; Miura, Masaru; Fukuda, Yoshimasa; Takemura, Koichi; Tokunaga, Katsuto; Matsuzawa, Yūji

doi:10.1038/nm0796-800

Cited by 836 publications

(511 citation statements)

References 20 publications

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“…6,7,16 Yet, the observation of similar and minor PAI-1 mRNA expression in native human visceral and subcutaneous adipose tissue 7,17,18 is not consistent with such a mechanism. Moreover, we found strong indications that the observed PAI-1 release from adipose tissue explants on in vitro incubation relates to an incubation artifact and may not necessarily reflect the in vivo situation.…”

Section: Discussionmentioning

confidence: 93%

“…Despite a large body of epidemiological and experimental evidence in support of a direct link between (visceral) adipose tissue and plasma PAI-1 levels, 1,2,6 clinical evidence is less obvious and the molecular basis for the association between (visceral) adipose tissue and plasma PAI-1 levels in man is still unclear. 7 The most obvious explanation for the association between plasma PAI-1 levels and visceral adipose tissue is a direct link in which the elevated plasma PAI-1 levels in (visceral) obesity result from PAI-1 release from (visceral) fat mass.…”

Section: Introductionmentioning

confidence: 99%

“…7 The most obvious explanation for the association between plasma PAI-1 levels and visceral adipose tissue is a direct link in which the elevated plasma PAI-1 levels in (visceral) obesity result from PAI-1 release from (visceral) fat mass. 6 Support for such a direct association largely stems from animal and in vitro data, 6 but evidence for such a mechanism in humans is still missing. A second, more indirect, explanation for the relationship is release of an inflammatory 'mediator', such as tumor necrosis factor (TNF)a or IL-1, 8 from visceral fat, which induces PAI-1 production outside visceral fat.…”

Section: Introductionmentioning

confidence: 99%

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Human visceral adipose tissue and the plasminogen activator inhibitor type 1

Lindeman

Pijl

Toet³

et al. 2007

Int J Obes

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Objective: The objective of this study was to systematically evaluate the molecular basis of the association between visceral fat mass and plasma plasminogen activator inhibitor-1 (PAI-1) levels in man. Design: A comprehensive approach comprising observational, in vitro, and human intervention studies. Measurements and results:We confirmed an exclusive relationship between visceral fat and plasma PAI-1 levels (r ¼ 0.79, Po0.001) and corroborated preferential PAI-1 release from adipose tissue explants. Yet, messenger RNA analysis and in vivo measurement of PAI-1 release from visceral fat (AV-differences over the omentum) not only excluded visceral adipose tissue as a relevant source of circulating PAI-1, but also excluded visceral fat as a significant source of proinflammatory mediators such as tumor necrosis factor-a, IL-1 or transforming growth factor-b that could induce PAI-1 expression in tissues other than visceral fat. Short-term interventions with acipimox and growth hormone (GH) as well as statistical evaluation excluded free fatty acids and GH as metabolic links. Further analysis of the metabolic data in a stepwise regression model indicated that plasma PAI-1 levels and visceral fat rather are co-correlates that both relate to impaired lipid handling. Conclusion: Our PAI-1 studies show that visceral fat mass and plasma PAI-1 levels are co-correlated rather than causatively related, with lipid load as common denominator.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human visceral adipose tissue and the plasminogen activator inhibitor type 1

Lindeman

Pijl

Toet³

et al. 2007

Int J Obes

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“…This seems to be driven from the macrophage by TNF-α and from the adipocyte by increased NEFA [16]. TNF-α also enhances the production of PAI-1 from the adipocyte and other cell lines [17].…”

Section: Neel Revisitedmentioning

confidence: 97%

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Scott

Grant

2006

Diabetologia

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The modern epidemic of obesity and insulin resistance with cardiovascular risk factor clustering is related to the development of type 2 diabetes and cardiovascular disease. Over 40 years ago, Neel postulated that insulin resistance should confer survival benefit. Extrapolating Neel's hypothesis, we propose that the cluster of associated abnormalities also confers survival benefit and is related to metabolic responses seen in seasonally responsive animals. Weight gain in preparation for winter is accompanied by a range of acute metabolic changes virtually identical to the long-term changes seen in type 2 diabetes. In seasonal animals the responses are acute, physiological and protective. In man, similar responses that would once have conferred survival benefit have become chronic, pathological and harmful in modern life. We hypothesise that type 2 diabetes and cardiovascular disease in man are the result of chronic and inappropriate pinealhypothalamic-adipocyte interactions biologically related to seasonal change.Keywords Adipocyte . Cardiovascular disease . Circadian and circannual rhythm . Clock genes . Hypothalamus . Inflammation . Insulin resistance . Melatonin . Metabolic syndrome . Seasonality . Type 2 diabetes Neel revisitedThe world is currently in the midst of an epidemic of type 2 diabetes, and around 300 million individuals are predicted to develop this disorder by the year 2025 [1]. The close biological relationship between diabetes and cardiovascular disease has focused attention on the common genetic and environmental antecedents of these conditions-the common soil hypothesis [2]-but the pathophysiological basis of these associations remains obscure. In 1962, Neel proposed the thrifty genotype hypothesis, which postulated that insulin overproduction must at one time have had a beneficial effect, in that it would provide 'an important energy conserving mechanism when food intake was irregular and obesity rare' [3]. Although Neel recognised insulin antagonism rather than insulin resistance, he hypothesised that the combination of obesity with increased insulin (or the presence of insulin antagonists) would lead to the development of diabetes. With hindsight, Neel was essentially speculating on the potential metabolic benefits of insulin resistance. The recognition in the last 20 years of an insulin resistance risk cluster [4] indicates that, under certain circumstances, elements of the risk cluster should also be beneficial to the survival of the organism, a response that, by analogy with Neel's original hypothesis, may coincidentally lead to the development of cardiovascular disease in times of plenty. The development of both insulin resistance and inflammation are physiological responses to increasing adiposity that, by definition, should be beneficial to the survival of the organism. The observation that the chronic metabolic milieu associated with type 2 diabetes is harmful raises the possibility that the adipocyte response to fat loading is beneficial when acute and short-lived, as is o...

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“…During the last 5 years it has become widely accepted that adipocytes do function as endocrine cells by secreting a variety of highly active molecules. These so-called adipocytokines [1] are secreted from the adipose tissue into the blood stream. …”

mentioning

confidence: 99%

Identification of regulatory elements in the human adipose most abundant gene transcript-1 (apM-1) promoter: role of SP1/SP3 and TNF-? as regulatory pathways

et al. 2003

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Aims/hypothesis. The human adipocyte-specific apM-1 (adipose most abundant gene transcript-1) gene encodes for a secretory protein of the adipose tissue that seems to play a role in the pathogenesis of obesityrelated insulin resistance and its expression is inhibited by TNF-α. Our aim was to characterize the tissuespecific regulation of the recently cloned apM-1 promoter and the mechanisms of TNF-α-induced downregulation of the apM-1 gene. Methods. We characterised the apM-1 gene by electrophoretic mobility shift assays (EMSA) and luciferase reporter gene assays (LRA). Results. Although several putative binding sites for transcription factors known to be involved in adipogenesis such as C/EBP and PPARγ are present in the promoter, we could not detect any binding of these nuclear proteins from differentiated adipocytes. However, a proximal SP1 binding site specifically binds both, recombinant SP1 protein and SP1 derived from adipocyte nuclear extracts. Since the expression of SP1 during adipocyte differentiation has not yet been analysed, we could show by using EMSA, that binding activity of SP1 is increased during adipocyte differentiation. The stimulatory activity of SP1 was confirmed in LRA by cotransfection experiments in S2 Schneider cells lacking endogenous SP factors. An inhibitory activity of SP3 on the stimulatory effect of SP1 could be confirmed in LRA by contransfection experiments in adipocytes. Nuclear extracts from adipocytes incubated with TNF-α showed a reduced binding activity of SP1. Conclusion/interpretation. SP1 is expressed and its binding activity is enhanced during adipocyte differentiation. SP1 has stimulatory effects, SP3 has inhibitory effects on apM-1 promoter activity, mediated by a proximal SP1 binding site. The mechanism of TNF-α-induced inhibition of apM-1 gene expression is, at least in part, due to a decrease of transcriptional SP1 binding activity caused by TNF-α and thus provides a new mechanism of TNF-α-dependent signalling. [Diabetologia (2002[Diabetologia ( ) 45:1425[Diabetologia ( -1433 Keywords apM-1, adipocyte, promoter, SP1, SP3, TNF-α, transcription, differentiation, diabetes, obesity. The adipose tissue has been considered as a special type of connective tissue, that stores energy in the form of triglycerides and releases energy in the form of non-esterified fatty acids whenever needed. However, increasing evidence suggests that the adipose tissue produces and secretes several highly active molecules. During the last 5 years it has become widely accepted that adipocytes do function as endocrine cells by secreting a variety of highly active molecules. These so-called adipocytokines [1] are secreted from the adipose tissue into the blood stream.

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Enhanced expression of PAI–1 in visceral fat: Possible contributor to vascular disease in obeisty

Cited by 836 publications

References 20 publications

Human visceral adipose tissue and the plasminogen activator inhibitor type 1

Human visceral adipose tissue and the plasminogen activator inhibitor type 1

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Identification of regulatory elements in the human adipose most abundant gene transcript-1 (apM-1) promoter: role of SP1/SP3 and TNF-? as regulatory pathways

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