Stromal Cells Are the Main Plasminogen Activator Inhibitor-1-Producing Cells in Human Fat

Bastelica, Delphine; Morange, Pierre‐Emmanuel; Berthet, B.; Borghi, H.; Lacroix, Odile; Grino, Michel; Juhan‐Vague, I.; Alessi, Marie‐Christine

doi:10.1161/hq0102.101552

Cited by 170 publications

(107 citation statements)

References 36 publications

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“…2A, adipose tissue expression of TSP1 and PAI-1 mRNAs associated positively (r ϭ 0.48, P Ͻ 0.0001, n ϭ 80). Interestingly, PAI-1 gene expression was higher in the SVF compared with the adipocyte fraction (1.76 Ϯ 0.32 and 0.49 Ϯ 0.14, respectively), consistent with previous reports (32), that is reciprocal to the expression of the TSP1 gene (shown in Table 1), which predominates in the adipocyte fraction. A positive correlation was also observed on examining the association of adipose tissue TSP1 mRNA and circulating PAI-1 levels (r ϭ 0.36, P Ͻ 0.02, n ϭ 41, Fig.…”

Section: Resultssupporting

confidence: 92%

Thrombospondin-1 Is an Adipokine Associated With Obesity, Adipose Inflammation, and Insulin Resistance

et al. 2008

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OBJECTIVE-We examined the relationship between the expression of thrombospondin (TSP)1, an antiangiogenic factor and regulator of transforming growth factor-␤ activity, obesity, adipose inflammation, and insulin resistance.RESEARCH DESIGN AND METHODS-TSP1 gene expression was quantified in subcutaneous adipose tissue (SAT) of 86 nondiabetic subjects covering a wide range of BMI and insulin sensitivity, from visceral adipose (VAT) and SAT from 14 surgical patients and from 38 subjects with impaired glucose tolerance randomized to receive either pioglitazone or metformin for 10 weeks. An adipocyte culture system was also used to assess the effects of pioglitazone and coculture with macrophages on TSP1 gene expression. RESULTS-TSP1mRNA was significantly associated with obesity (BMI) and insulin resistance (low insulin sensitivity index). Relatively strong positive associations were seen with markers of inflammation, including CD68, macrophage chemoattractant protein-1, and plasminogen activator inhibitor (PAI)-1 mRNA (r Ն 0.46, P ϭ 0.001 for each), that remained significant after controlling for BMI and S i . However, TSP1 mRNA was preferentially expressed in adipocyte fraction, whereas inflammatory markers predominated in stromal vascular fraction. Coculture of adipocytes and macrophages augmented TSP1 gene expression and secretion from both cell types. Pioglitazone (not metformin) treatment resulted in a 54% decrease (P Ͻ 0.04) in adipose TSP gene expression, as did in vitro pioglitazone treatment of adipocytes.CONCLUSIONS-TSP1 is a true adipokine that is highly expressed in obese, insulin-resistant subjects; is highly correlated with adipose inflammation; and is decreased by pioglitazone. TSP1 is an important link between adipocytes and macrophagedriven adipose tissue inflammation and may mediate the elevation of PAI-1 that promotes a prothrombotic state. Diabetes 57: 432-439, 2008

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Section: Resultssupporting

confidence: 92%

Thrombospondin-1 Is an Adipokine Associated With Obesity, Adipose Inflammation, and Insulin Resistance

et al. 2008

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“…By contrast, PAI-1 was expressed predominantly in the SVF (Fig. 1c), consistent with the fact that it is mainly expressed by adipose tissue macrophages [24]; leptin was expressed 1,000-fold higher in the AF than in the SVF (Fig. 1d) and adiponectin 400-fold higher (Fig.…”

Section: Cd40 Is Expressed By Human Adipocytessupporting

confidence: 82%

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

et al. 2009

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Aims/hypothesis Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation. Methods CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture. Results CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal-vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell-cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes. Conclusions/interpretation Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.

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“…For stromal tissue close to adipocytes, the stained stromal area was divided by the number of adipocytes counted in the examined field (labeled stromal surface/ adipocyte). Antibody against leptin was used as positive control of adipocyte staining and immunohistochemistry was performed as already described (22).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Leptin antisense riboprobe was used as previously described as a positive control of adipocyte labeling (22).…”

Section: In Situ Hybridizationmentioning

confidence: 99%

“…Cultures of SC preadipocytes, issued from five subjects among the lean population tissue, undergoing differentiation were prepared as previously described (22). After collagenase digestion and erythrocyte lysis, stromal cells isolated from adipocytes were resuspended in DME/ HAMF12 medium supplemented with 15 mmol/l NaH 2 CO 3 , 33 mmol/l biotin, and 17 mmol/l panthotenate.…”

Section: Am Secretion During In Vitro Preadipocytes Differentiationmentioning

confidence: 99%

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Expression of adrenomedullin in adipose tissue of lean and obese women

et al. 2006

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Objective: Adrenomedullin (AM), a potent vasodilatator and antioxidative peptide, was shown recently to be expressed by adipose tissue. The aim of our study was to investigate the precise localization of AM within human adipose tissue, and to examine AM regulation in obesity. Design: Subcutaneous (SC) and omental (OM) adipose tissues from 9 lean and 13 obese women were profiled for AM expression changes. Preadipocytes from human adipose tissue were isolated and differentiated under defined adipogenic conditions. Methods: AM expression was analyzed by immunohistochemistry, in situ hybridization and quantitative RT-PCR. Results: A strong AM expression was observed in vessel walls, stromal cell clusters and isolated stromal cells, some of them being CD 68 positive, whereas mature adipocytes were not labeled. Calcitonin receptor-like receptor and receptor activity-modifying proteins (RAMP) 2 and RAMP 3 were expressed in vessel walls. In vitro, preadipocytes of early differentiation stages spontaneously secreted AM. No difference in AM localization was found between SC and OM adipose tissue. AM levels in SC tissue did not differ between lean and obese subjects. By contrast, AM levels in OM tissue were significantly higher in obese as compared with lean women. Moreover, we found a positive relationship between OM AM and tumor necrosis factor a mRNA levels and AM-immunoreactive area in OM tissue followed the features of the metabolic syndrome. Conclusion: Stromal cells from human adipose tissue, including macrophages, produce AM. Its synthesis increased in the OM territory during obesity and paralleled the features of the metabolic syndrome. Therefore, AM should be considered as a new member of the adipokine family.

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Stromal Cells Are the Main Plasminogen Activator Inhibitor-1-Producing Cells in Human Fat

Cited by 170 publications

References 36 publications

Thrombospondin-1 Is an Adipokine Associated With Obesity, Adipose Inflammation, and Insulin Resistance

Thrombospondin-1 Is an Adipokine Associated With Obesity, Adipose Inflammation, and Insulin Resistance

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

Expression of adrenomedullin in adipose tissue of lean and obese women

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