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

Samad, Fahumiya; Uysal, K. Teoman; Wiesbrock, S M; Pandey, Manjula; Hotamışlıgil, Gökhan S.; Loskutoff, David J.

doi:10.1073/pnas.96.12.6902

Cited by 213 publications

(175 citation statements)

References 54 publications

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Section: Discussionmentioning

confidence: 99%

“…TNF-␣ and TGF-␤ are potent inducers of PAI-1 expression, and in severe obesity a proportional increase in adipose tissue PAI-1 and TGF-␤ has been reported in humans and mice (25,26). It has been further suggested that increased TNF-␣ provides the common link between insulin resistance and elevated PAI-1 and TGF-␤ expression in obesity (26). However, in adipocytes from FIRKO mice, PAI-1 and TGF-␤ gene expression were found to be up-regulated despite significantly lower TNF-␣ expression, suggesting that impaired insulin signaling can affect PAI-1 and TGF-␤ gene expression independently of increased TNF-␣ expression.…”

Section: Discussionmentioning

confidence: 99%

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Intrinsic Heterogeneity in Adipose Tissue of Fat-specific Insulin Receptor Knock-out Mice Is Associated with Differences in Patterns of Gene Expression

Blüher

Patti

Gesta

et al. 2004

Journal of Biological Chemistry

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Mice with a fat-specific insulin receptor knock-out (FIRKO) have reduced adipose tissue mass, are protected against obesity, and have an extended life span. White adipose tissue of FIRKO mice is also characterized by a polarization into two major populations of adipocytes, one small (<50 m) and one large (>100 m), which differ with regard to basal triglyceride synthesis and lipolysis, as well as in the expression of fatty acid synthase, sterol regulatory element-binding protein 1c, and CCAAT/enhancer-binding protein ␣ (C/EBP-␣). Gene expression analysis using RNA isolated from large and small adipocytes of FIRKO and control (IR lox/lox) mice was performed on oligonucleotide microarrays. Of the 12,488 genes/expressed sequence tags represented, 111 genes were expressed differentially in the four populations of adipocytes at the p < 0.001 level. These alterations exhibited 10 defined patterns and occurred in response to two distinct regulatory effects. 63 genes were identified as changed in expression depending primarily upon adipocyte size, including C/EBP-␣, C/EBP-␦, superoxide dismutase 3, and the platelet-derived growth factor receptor. 48 genes were regulated primarily by impairment of insulin signaling, including transforming growth factor ␤, interferon ␥, insulin-like growth factor I receptor, activating transcription factor 3, aldehyde dehydrogenase 2, and protein kinase C␦. These data suggest an intrinsic heterogeneity of adipocytes with differences in gene expression related to adipocyte size and insulin signaling.Adipocytes play a central role in energy balance, both as a reservoir, storing and releasing fuel, and as endocrine cells, secreting factors that regulate whole body energy metabolism (1). The loss of insulin action selectively in adipose tissue in mice with a fat-specific insulin receptor knock-out (FIRKO) 1 leads to profound changes in cellular function, including changes in glucose metabolism, lipid storage, and protein expression (2). We reported previously that FIRKO mice have markedly reduced fat mass and whole body triglyceride stores and are protected from gold thioglucose-induced and age-related obesity, as well as the associated glucose intolerance (2). These changes are associated with increased longevity of these mice (3). FIRKO mice also exhibit a heterogeneity in fat cell size with polarization into small (diameter Ͻ50 m) and large (diameter Ͼ100 m) subclasses of adipocytes (2). This polarization by cell size of adipose tissue is not unique to the FIRKO model. Targeted disruption of the hormone-sensitive lipase also causes reduced body fat mass and heterogeneity of adipocytes in white adipose tissue (WAT) with a population of larger adipocytes, which is sensitive to lipid accumulation, and a population of small adipocytes, which is not (4, 5). These results suggest that adipocytes, even within a single depot of WAT, may not be of a single lineage or type (6).Using a candidate gene/protein approach we found that the heterogeneity of WAT in FIRKO mice is accompanied by changes in the...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intrinsic Heterogeneity in Adipose Tissue of Fat-specific Insulin Receptor Knock-out Mice Is Associated with Differences in Patterns of Gene Expression

Blüher

Patti

Gesta

et al. 2004

Journal of Biological Chemistry

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“…Moreover, in adipocytes treated with TNF-␣, the IR accumulated less in the detergent-insoluble low-density membrane fractions (microdomains) and shifted to the high-density fractions, suggesting a translocation of IR from caveolar to noncaveolar fractions (40). TNF-␣ is a potent inducer of insulin resistance (41) and PAI-1 gene expression (42). It is chronically elevated in conditions of obesity and is a major culprit in the pathogenesis of obesity-driven insulin resistance (41).…”

Section: Discussionmentioning

confidence: 99%

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

Venugopal

Hanashiro

Yang

et al. 2004

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

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Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathogenesis of obesity-driven type 2 diabetes mellitus and associated cardiovascular complications. Here, we show that perturbation of caveolar microdomains leads to insulin resistance and concomitant up-regulation of PAI-1 in 3T3L1 adipocytes. We present several lines of evidence showing that the phosphatidylinositol 3-kinase (PI3K) pathway negatively regulates PAI-1 gene expression. Insulin-induced PAI-1 gene expression is up-regulated by a specific inhibitor of PI3K. In addition, serum PAI-1 level is elevated in protein kinase B␣-deficient mice, whereas it is reduced in p70 ribosomal S6 kinase 1-deficient mice. The PI3K pathway phosphorylates retinoblastoma protein (pRB), known to release free E2 (adenoviral protein) factor (E2F), which we have previously demonstrated to be a transcriptional repressor of PAI-1 gene expression. Accordingly, cell-penetrating peptides that disrupt pRB-E2F interaction, and thereby release free E2F, are able to suppress PAI-1 levels that are elevated during insulin-resistant conditions. This study identifies a caveolar-dependent signal pathway that up-regulates PAI-1 in insulin-resistant adipocytes and proposes a previously undescribed pharmacological paradigm of disrupting pRB-E2F interaction to suppress PAI-1 levels. diabetes T ype 2 diabetes mellitus (T2DM) is characterized by insulin resistance, where the insulin receptor (IR) fails to elicit the metabolic signaling that is required for glucose metabolism and energy homeostasis. In insulin-sensitive tissues, the IR transduces two main signaling cascades: a metabolic signaling that is responsible for glucose uptake and glycogen synthesis and a mitogenic signaling that is responsible for cell proliferation and growth. The IR substrate (IRS)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) and Cbl-CAP-Flotillin pathways represents the major metabolic signaling, whereas the Shc-Rasextracellular regulated kinase (Erk) pathway represents the major mitogenic signaling (1). Both in animal models and clinical T2DM subjects, a selective impairment of metabolic signaling has been observed, whereas mitogenic signaling is more or less unaffected (2-4).Obesity is prominent among the plethora of factors that leads to the development of T2DM, although the molecular mechanism underlying the pathogenesis of obesity-driven T2DM is not well understood. Comparative analysis of large and small fat cells within the same fat pad reveals a 2-fold reduction in the levels of plasma membrane cholesterol in large fat cells, suggesting that a decrease in membrane cholesterol is characteristic of adipocyte hypertrophy per se (5). Recently, it has been proposed that the protein levels of caveolin-1 and -3 are inversely correlated to the body-mass index. § Plasma membrane cholesterol (6) and caveolins (7) are indispensable for the structural and functional integrity of caveolar microdomains. We therefore reasoned that obesity might lead to caveolar dysfunction. Because the IR...

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“…18 We have also recently demonstrated that perivascular adipose tissue releases a factor that significantly modulates vascular response to constrictive stimuli. 19 In addition, obese individuals have high circulating plasma levels of a range of inflammatory markers and thrombogenic factors produced by adipose tissue including TNF-alpha, 20 interleukin-1 and fibrinogen. These factors, which can be reduced by weight loss, are likely to contribute to vascular damage in obese individuals.…”

Section: Adipose Tissue As An Endocrine Organmentioning

confidence: 99%

Adipose tissue: a mediator of cardiovascular risk

Sharma

2002

Int J Obes

117

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Two key findings regarding the cardiovascular risks associated with obesity have emerged in recent years: one relates to the importance of visceral obesity as a risk factor for cardiovascular disease, and the other to the recognition that adipose tissue can be regarded as a large endocrine organ that directly contributes to cardiovascular risk by secreting a number of molecules known to modulate vascular, metabolic, inflammatory and other functional aspects of the cardiovascular system. Therefore, abdominal fat deposition, which is characterized by increase in waist circumference, should be the target of clinical intervention in obese individuals.

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

Cited by 213 publications

References 54 publications

Intrinsic Heterogeneity in Adipose Tissue of Fat-specific Insulin Receptor Knock-out Mice Is Associated with Differences in Patterns of Gene Expression

Intrinsic Heterogeneity in Adipose Tissue of Fat-specific Insulin Receptor Knock-out Mice Is Associated with Differences in Patterns of Gene Expression

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

Adipose tissue: a mediator of cardiovascular risk

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