M. Tonoli

Visceral Fat Accumulation and Its Relation to Plasma Hemostatic Factors in Healthy Men

The associations between abdominal visceral fat and the plasma hemostatic system were examined in 38-year-old healthy men (n=52) with a wide range of fatness and fat distribution. Plasma hemostatic factors and metabolic parameters, including glucose tolerance, were measured, and body fatness and adipose tissue distribution were assessed by using computed tomography. The men with more visceral fat (ie, higher than the median value [n=26]) had a less favorable metabolic profile than the men with less visceral fat (n=26). They also had significantly (P<.05) higher plasma fibrinogen, factor VIII clotting activity, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor-1 (PAI-1) activity (19.2+/-2.4 versus 8.5+/-1.6 AU/mL, P<.001) and lower basal tissue-type plasminogen activator activity. After adjustment for plasma insulin, the men with larger abdominal visceral fat area still had significantly higher plasma PAI-1 activity, but no difference was found in any of the other hemostatic factors. In multiple linear regression analysis, abdominal visceral fat area was a positive predictor of plasma PAI-1 activity, but it failed to show any significant association with other hemostatic factors after controlling for plasma insulin. These results suggest the presence of relationships between abdominal visceral fat and several plasma hemostatic factors that are largely mediated by concomitant alterations in plasma insulin concentration. In addition, our results suggest that abdominal accumulation of visceral fat is an independent predictor of plasma PAI-1 activity.

Expression of plasminogen activator inhibitor-1 in human adipose tissue : a role for TNF-α?

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.

The white blood cell count: its relationship to plasma insulin and other cardiovascular risk factors in healthy male individuals

Targher G, Seidell JC, Tonoli M, Muggeo M, De Sandre G, Cigolini M (Division of Endocrinology and Metabolic Diseases, Institute of Clinical Medicine, University of Verona, Italy; and Department of Chronic Diseases and Environmental Epidemiology‐RIVM, Bilthoven, The Netherlands). The white blood cell count: relationship to plasma insulin and other cardiovascular risk factors in healthy males. J Intern Med 1996; 239: 435–41.

Relationships of blood pressure to fibrinolysis: influence of anthropometry, metabolic profile and behavioural variables

Objective: To investigate the relationship between blood pressure and the plasma fibrinolytic system and to verify whether this association was independent or mediated by one or more potential confounding factor. Design: A random sample of 94 males aged 38 years subdivided into normotensives, hypertensives and those hypertensives with the highest blood pressure values. Methods: Overall and regional obesity, blood lipids, fasting and 2-h post-load glucose, C-peptide and insulin levels, and main behavioural variables, including adipose tissue fatty acid composition (an objective index of dietary fat intake), were measured. The plasma fibrinolytic system was evaluated by determining activities and total plasma concentrations of both tissue-type plasminogen activator before and after venous occlusion, and its inhibitor plasminogen activator inhibitor type-1 (PAI-1). Results: PAI-1 activity was significantly higher in the hypertensives than in the normotensives. PAI-1 antigen tended to parallel PAI-1 activity, and levels of tissue-type plasminogen activator antigen and activity tended to be lower in the hypertensives at baseline and after venous occlusion, but not significantly different from those in the normotensives. The hypertensives also had significantly higher body mass index and body fat content (measured by bio-impedance), increased plasma triglycerides, uric acid, fasting and 2-h glucose, C-peptide and insulin concentrations. In univariate linear regression analysis both systolic and diastolic blood pressures were found to be positively correlated with PAI-1 levels (r=0.27, P< 0.01, for both). This correlation was maintained after adjustment for total body fat, fasting glucose, fasting insulin concentration or adipose tissue ct-linolenic acid; however, it was no longer significant after adjustment for plasma 2-h insulin, 2-h C-peptide, 2-h glucose or triglyceride levels. Multivariate regression analysis revealed that only 2-h insulin and triglyceride concentration showed an independent association with PAI-1 levels. Conclusions: This study confirms that, in 38-year-old males, hypertension is associated with increased PAI-1 activity. It supports the possibility that the relationship between blood pressure and PAI-1 may reflect the overall effect of the insulin resistance syndrome (in particular hyperinsulinaemia and hypertriglyceridaemia) rather than a direct effect of blood pressure on the fibrinolytic system.

Plasma factor VII and its relation to adipose tissue fatty acids and other atherogenic risk factors in healthy men

In this study the authors examined the relationships of plasma factor VII (F–VII) to adipose tissue fatty acid composition, as an objective index of the habitual dietary fat intake, as well as to a number of other atherogenic risk factors in 60 healthy male volunteers (aged 38 years). Significant positive correlations were found between plasma F‐VII [measured as antigen (F‐VIIAg) and coagulant activity, using bovine thromboplastin (F‐VIIbt)] and body mass index (BMI), waist–thigh girth ratio (WTR), cigarette smoking and plasma triglyceride concentration. After adjustment for BMI, only plasma triglycerides remained positively correlated with F‐VII (r = 0.27, P = 0.03, and r = 0.29, P < 0.01, for F‐VIIbt and F‐VIIAg respectively). A significant positive relation was found between F‐VII and the total proportion of fatty acid as monounsaturated fatty acid (r = 0.26, P < 0.05, for F‐VIIAg), whereas inverse relations were found between F‐VII, the total proportion of fatty acid as polyunsaturated fatty acid (r = − 0.26 and r = − 0.25, P < 0.05, for F‐VIIbt and F‐VIIAg respectively), polyunsaturated–saturated fat ratio (r = − 0.25, P < 0.05, for F‐VIIbt) and, more significantly, between F‐VII and adipose‐tissue α‐linolenic acid (r = − 0.29, P < 0.01, for F‐VIIbt and r = − 0.49, P < 0.001, for F‐VIIAg). All these correlations remained significant after matching for BMI. In a multiple linear regression analysis, only adipose tissue α‐linolenic acid was a negative and independent predictor of F‐VIIAg (P = 0.004) and, at borderline significance, of F‐VIIbt (P = 0.061) when allowance was made for BMI, WTR, smoking and plasma triglycerides. In conclusion, this study shows significant relations between F‐VII and adipose tissue fatty acid composition in healthy male individuals; it supports the possibility that adipose tissue poly‐ unsaturated fatty acids, derived from dietary intake, play a role in the relation between F‐VII and coronary heart disease (CHD), thus suggesting that high dietary polyunsaturated fatty acid intake (especially α‐linolenic acid) may reduce the risk for CHD by an improvement of a number of risk factors, including a lowering of plasma F‐VII (both activity and antigen).