Daniël R Faber

University Medical Center Utrecht, Utrecht, Provincie Utrecht, Netherlands

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Publications (9)29.6 Total impact

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    ABSTRACT: We investigated whether plasma ferritin levels through the pro-inflammatory effects of free iron are associated with adipose tissue dysfunction in a relevant population of patients with manifest vascular disease who would potentially benefit the most from further aetiological insights. In a cohort of 355 patients with vascular diseases, the association between plasma ferritin and adiponectin levels was quantified using linear regression analysis. Interleukin-6 and adiponectin levels were measured in medium from pre-adipocytes and adipocytes after incubation with increasing concentrations of Fe(III)-citrate and after co-incubation with iron chelators or radical scavengers. Increasing ferritin plasma concentrations were not related to plasma adiponectin levels in patients without (β -0·13; 95% CI -0·30 to 0·04) or with the metabolic syndrome (β -0·04; 95% CI -0·17 to 0·10). Similar results were found in patients who developed a new cardiovascular event in the follow-up period. In vitro, incubation with increasing concentrations of Fe(III)-citrate-induced inflammation in pre-adipocyte cultures as witnessed by increased IL-6 secretion at 30 μm Fe(III)-citrate vs. control (500 ± 98 pg/mL vs. 194 ± 31 pg/mL, P = 0·03). Co-incubation of pre-adipocytes with iron chelators or radical scavengers prevented this inflammatory response. Incubation of adipocytes with 30 μm Fe(III)-citrate did not influence adiponectin secretion compared with control. In patients with vascular disease, there is no association between plasma ferritin and adiponectin levels. In vitro, free iron induces an inflammatory response in pre-adipocytes, but not in adipocytes. This response was blocked by co-incubation with iron chelators or radical scavengers. Adiponectin secretion by adipocytes was not influenced by free iron.
    European Journal of Clinical Investigation 12/2013; 43(12):1240-1249. · 3.37 Impact Factor
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    ABSTRACT: BACKGROUND: Increased production of chemokines by adipose tissue and defective adipose tissue oxygenation as a result of obesity may induce leucocyte infiltration and subsequent systemic inflammation. OBJECTIVES: 1-To determine the relation between the amount of visceral and subcutaneous adipose tissue and the chemokine interferon-γ-inducible protein 10 (IP-10) and angiogenic factor hepatocyte growth factor (HGF). 2-To determine the relation between the metabolic syndrome and IP-10 as well as HGF. METHODS: Patients originated from the Secondary Manifestations of ARTerial disease (SMART) cohort. In this study, a cohort of 1251 patients with manifest vascular disease was included. Subcutaneous and visceral adipose tissue thickness (SAT and VAT respectively) were measured ultrasonographically. IP-10 and HGF concentrations were measured with Luminex multiplex immuno assay in addition to fasting metabolic parameters. Linear regression analyses with adjustments for age, gender, smoking, estimated glomerular filtration rate, type 2 diabetes mellitus and medication use were applied to quantify the relations between adiposity or metabolic syndrome and IP-10 and HGF concentrations. RESULTS: VAT was significantly associated with (log)IP-10 and (log)HGF, reflected by significant higher β-values in VAT quartile 4 compared with VAT quartile 1 (reference): β0.155 (95%CI:0.073-0.237) for IP-10 and β0.147 (95%CI:0.076-0.218) for HGF. Per standard deviation increase in VAT, (log)IP-10 levels increased with 0.057 pg/mL (95%CI:0.027-0.087) and (log)HGF increased with 0.051 pg/mL (95%CI:0.025-0.077). Effect estimates were not affected by including body mass index(BMI) in the model. In contrast, SAT was not associated with IP-10 and HGF. Furthermore, the presence of the metabolic syndrome was associated with IP-10 and HGF. CONCLUSIONS: Visceral adipose tissue but not subcutaneous adipose tissue is significantly associated with circulating levels of IP-10 and HGF, irrespective of BMI.
    European Journal of Clinical Investigation 02/2013; · 3.37 Impact Factor
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    ABSTRACT: Background:Obesity is associated with a prothrombotic state, which may contribute to the increased risk of thrombotic events.Objective:To assess the effects of (pre)adipocyte-derived adipokines on fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) production by hepatocytes.Methods:HepG2 hepatocytes were incubated with conditioned media (CM) derived from preadipocytes and adipocytes, which had been untreated or prestimulated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β or IL-6. After 24 h, supernatants and cell lysates were harvested for measurement of fibrinogen, PAI-1 and TF.Results:(Pre)adipocyte CM significantly enhanced the production of PAI-1 by HepG2 cells 2.5- to 4.4-fold. CM from cytokine-stimulated (pre)adipocytes significantly induced fibrinogen secretion 1.5- to 4.2-fold. TF production was not affected by the CM. After specific depletion of TNF-α, IL-1β or IL-6 from the CM, IL-6 was shown to be the most prominent stimulus of fibrinogen secretion and IL-1β of PAI-1 secretion. In addition, fibrinogen, PAI-1 and tissue factor production was evaluated by direct stimulation of HepG2 cells with TNF-α, IL-1β or IL-6. IL-6 enhanced fibrinogen synthesis 4.3-fold (P<0.01), whereas IL-1β induced PAI-1 production 5.0-fold (P<0.01). Gene expression analyses showed that TNF-α and IL-1β stimulate the adipocyte expression of TNF-α, IL-1β and IL-6. Cytokine stimulation of adipocytes may thus have induced an inflammatory response, which may have stimulated fibrinogen and PAI-1 production by HepG2 cells more potently.Conclusions:SGBS (pre)adipocytes release cytokines that increase the production of fibrinogen and PAI-1 by HepG2 cells. IL-6 and IL-1β produced by (pre)adipocytes were the strongest inducers of fibrinogen and PAI-1 secretion, respectively.
    Nutrition & Diabetes 01/2012; 2:e52.
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    ABSTRACT: Adipose tissue dysfunction is associated with inflammation, type 2 diabetes mellitus and vascular diseases. Visceral adipose tissue (VAT)-derived adipokines, which are released in the portal circulation may influence liver metabolism. (1) To estimate the contribution of VAT and subcutaneous adipose tissue (SAT) on adipokine levels by measuring differences in adipokine concentrations between the portal draining inferior mesenteric vein and the subclavian vein. (2) To determine the relation of both VAT and SAT quantity and composition to mesenteric and systemic concentrations of adipokines. Cross-sectional cohort study. A total of 32 patients undergoing abdominal aortic surgery. A panel of 18 adipokines was measured in perioperatively obtained blood samples from the subclavian vein and the inferior mesenteric vein. Adipocyte size, macrophage infiltration and capillary density were measured in subcutaneous and mesenteric adipose tissue biopsies; SAT and VAT areas were measured on computed tomography images. Serum interferon-γ-inducible protein 10 (IP-10) and hepatocyte growth factor (HGF) concentrations were significantly higher in the inferior mesenteric vein vs the subclavian vein. SAT area (β -18; 95% confidence interval (CI) -35 to -2), subcutaneous adipocyte size (β -488; 95% CI -938 to -38) and SAT macrophages quantity (β -1439; 95% CI -2387 to -491) were negatively associated with adiponectin levels in the systemic circulation. SAT area was related to systemic concentrations of leptin. Mesenteric adiponectin concentrations were related to VAT area (β -20; 95% CI -35 to -5) and visceral adipocyte size (β -1076; 95% CI -1624 to -527). VAT area, adipocyte size and capillary density were related to systemic adiponectin concentrations. SAT and VAT quantities as well as morphologic characteristics of both adipose tissue depots are related to systemic and mesenteric adipokine concentrations. There were no differences in adipokine concentrations between the mesenteric and subclavian vein, except for higher IP-10 and HGF concentrations in the inferior mesenteric vein, indicating a possible contribution of VAT to IP-10 and HGF levels.
    International journal of obesity (2005) 11/2011; 36(8):1078-85. · 5.22 Impact Factor
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    ABSTRACT: To investigate whether levels of thyroid-stimulating hormone (TSH) within the normal range are associated with an increased risk of new vascular events and mortality in patients with clinical manifest vascular diseases and whether this relation is influenced by adiposity. Prospective cohort study in 2443 patients (1790 men and 653 women) with clinical manifest vascular disease and TSH levels in the normal range. Median follow up was 2.7 (interquartile range 1.4-3.9) years. Clinical endpoints of interest were: myocardial infarction, stroke, vascular death, and all-cause mortality. In patients with manifest vascular disease, the prevalence of (subclinical) hypothyroidism was 5.7%, while 3.6% had (subclinical) hyperthyroidism. An increase in 1 unit of TSH was associated with a 33% higher risk (HR 1.33; 95% CI 1.03-1.73) for the occurrence of myocardial infarction, adjusted for age, gender, renal function, and smoking. In patients with a body mass index (BMI) below the median of 26.7 kg/m(2) the HR per unit TSH for myocardial infarction was 1.55 (95% CI 1.08-2.21) compared to 1.18 (95% CI 0.81-1.71) in patients with a BMI ≥26.7 kg/m(2). Visceral adipose tissue thickness below the median (≤8.8 cm) was associated with higher HR per unit TSH for myocardial infarction (HR 1.69; 95% CI 1.21-2.35) compared to visceral adipose tissue thickness >8.9 cm (HR 1.00; 95% CI 0.66-1.49). There was no relation between TSH and risk of stroke, vascular death, the combined endpoint, or all-cause mortality. Higher TSH levels within the normal range are associated with an increased risk of myocardial infarction, in patients with clinical manifest vascular disease. This relation is most prominent in patients without visceral obesity.
    European journal of preventive cardiology. 07/2011; 19(4):864-73.
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    ABSTRACT: Physical exercise has multiple beneficial health effects. Yearly, over five million persons walk a pilgrimage in various parts of the World, and this number is increasing. Here we report the effects on vascular function and cardiovascular risk factors of a 12-day pilgrimage to Santiago de Compostela in Spain. Twenty-nine healthy male and female subjects between 40 and 70 years were included in the intervention group. The intervention consisted of the last 280 km of the pilgrim route to Santiago de Compostela. Twenty-nine control subjects were age- and gender-matched. Measures of endothelial function, vascular stiffness, autonomic function, and cardiovascular risk factors were measured 2 months and 2 weeks before the pilgrimage and 2 weeks and 2 months afterwards. During the pilgrimage cardiovascular risk factors, including weight, lipids, glucose and blood pressure were measured every other day. The mean daily walking distance during the pilgrimage was 23.42±0.80 km taking 5.39±0.36 h/day. From start to end, HDL-cholesterol increased (0.20±0.30 mmol/L; +15%), while LDL-cholesterol (-0.6±0.6 mmol/L; -17%) and weight (-1.4±1.8 kg; -2%) decreased. After an initial rise, blood pressure came back to baseline. Two months after the pilgrimage a 2.0 kg weight loss persisted compared to the controls. There was no change in any vascular function parameter compared to the controls. Walking a pilgrimage immediately influences major cardiovascular risk factors as a consequence of (strenuous) exercise and, likely, dietary changes. Two months after the pilgrimage these changes came back to baseline, except for weight loss. There was no effect on vascular function.
    Atherosclerosis 10/2010; 212(2):621-7. · 3.71 Impact Factor
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    ABSTRACT: Visceral adiposity is associated with cardiovascular risk factors and increased cardiovascular risk. Thyroid-stimulating hormone (TSH) levels in the normal range are associated with a higher risk of fatal coronary artery disease. We hypothesize that TSH levels in the normal range are associated with an increase in visceral adipose tissue (VAT) in patients with vascular diseases. In 2419 patients with vascular diseases, visceral fat thickness was analysed with ultrasonography. The association between TSH and VAT was quantified using linear regression analysis. Results are expressed as beta (β) regression coefficients with 95% confidence intervals. Adjustments were made for age, sex, current smoking and weight. Separate analyses were performed per quartile of age. β-coefficients for the relation between TSH and VAT (change per SD of 2·55 cm) was 0·085 (95% CI 0·012-0·157) in the highest quartile of age (range 67-80 years) when adjusted for age, gender and current smoking and remained statistical significant after further adjustment for weight (β 0·096 95% CI 0·034-0·157). Per SD change, the β-coefficient for TSH and VAT tissue was larger than for other measures of adiposity. In conclusion, higher TSH plasma levels in the normal range are associated with more VAT in patients with manifest vascular disease above the age of 66 years. No association was found between plasma TSH levels and weight or BMI. The relation between TSH levels and VAT may provide an explanation for the increased cardiovascular risk associated with elevated TSH plasma concentrations within the normal range.
    European Journal of Clinical Investigation 10/2010; 41(2):159-66. · 3.37 Impact Factor
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    ABSTRACT: Obesity is related to the development of vascular diseases and metabolic complications. Low grade inflammation is a key feature of central obesity, characterized by elevated plasma levels of C-reactive protein (CRP). We hypothesize that visceral adipose tissue contributes to systemic concentrations of CRP. In 2410 patients (1729 men and 681 women) with vascular diseases, subcutaneous and visceral fat masses were analyzed with ultrasonography. Metabolic parameters and CRP were measured in a fasting state. The association between fat measurements and plasma CRP was quantified using linear regression analysis. CRP levels were logarithmically transformed. Adjustments were made for age, smoking, type 2 diabetes mellitus, insulin resistance (HOMA-IR) and medication use. Visceral fat was categorized into quartiles (Q) ranging from 3.2 to 7.8 cm in Q1 (reference) to 11.0-19.8 cm in Q4 in men and 2.7-6.0 cm in Q1 (reference) to 9.0-17.4 cm in Q4 in women. beta-coefficients gradually increased across the quartiles from 0.07 (0.01-0.13) in Q2 to 0.25 (0.19-0.31) in Q4 in men and 0.17 (0.07-0.26) in Q2 to 0.42 (0.32-0.52) in Q4 in women, indicating 0.25 and 0.42 mg/l higher logarithmically transformed (log)CRP levels in Q4 compared to Q1 in respectively men and women. Per standard deviation increase of visceral fat, logCRP levels increased with 0.10 mg/l (0.07-0.12) in men and with 0.11 (0.15-0.19) in women. Likewise, in separate analyses waist circumference and body mass index showed a positive, but weaker association with logCRP levels across quartiles (in men: beta 0.21 (0.15-0.27) in Q4 for waist circumference and beta 0.23 (0.17-0.30) in Q4 for body mass index; in women: beta 0.32 (0.22-0.42) in Q4 for waist circumference and beta 0.32 (0.22-0.42) in Q4 for body mass index). In men subcutaneous fat was not associated with logCRP (beta-coefficients relative to Q1: -0.01 (-0.07 to -0.05), -0.01 (-0.07 to -0.05) and 0.05 (-0.01 to -0.11) in Q2 to Q4 respectively). In conclusion, visceral fat thickness is the strongest contributor to the systemic CRP concentrations in patients with vascular diseases.
    Atherosclerosis 09/2010; 212(1):274-80. · 3.71 Impact Factor
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    ABSTRACT: Obesity is associated with an increased incidence of insulin resistance (IR), type 2 diabetes mellitus and cardiovascular diseases. The increased risk for cardiovascular diseases could partly be caused by a prothrombotic state that exists because of abdominal obesity. Adipose tissue induces thrombocyte activation by the production of adipose tissue-derived hormones, often called adipokines, of which some such as leptin and adiponectin have been shown to directly interfere with platelet function. Increased adipose tissue mass induces IR and systemic low-grade inflammation, also affecting platelet function. It has been demonstrated that adipose tissue directly impairs fibrinolysis by the production of plasminogen activator inhibitor-1 and possibly thrombin-activatable fibrinolysis inhibitor. Adipose tissue may contribute to enhanced coagulation by direct tissue factor production, but hypercoagulability is likely to be primarily caused by affecting hepatic synthesis of the coagulation factors fibrinogen, factor VII, factor VIII and tissue factor, by releasing free fatty acids and pro-inflammatory cytokines (tumour necrosis factor-alpha, interleukin-1beta and interleukin-6) into the portal circulation and by inducing hepatic IR. Adipose tissue dysfunction could thus play a causal role in the prothrombotic state observed in obesity, by directly and indirectly affecting haemostasis, coagulation and fibrinolysis.
    Obesity Reviews 06/2009; 10(5):554-63. · 6.87 Impact Factor