Cystatin C, an endogenous inhibitor of cathepsin proteases has emerged as a biomarker of cardiovascular risk and reduced renal function. Epidemiological studies indicate that serum cystatin C increased in human obesity. Here, we evaluated the contribution of adipose tissue to this elevation, based on our previous observation that cystatin C is produced by in vitro differentiated human adipocytes. We measured serum cystatin C in 237 nonobese (age: 51 ± 0.8 years; BMI: 22.8 ± 0.11 kg/m2) and 248 obese subjects (age: 50 ± 0.8 years; BMI: 34.7 ± 0.29 kg/m2). Creatinine‐based estimated glomerular filtration rate (eGFR) was calculated to account for renal status. Cystatin C gene expression and secretion were determined on surgical adipose tissue biopsies in a distinct group of subjects. Serum cystatin C is elevated in obese subjects of both genders, independently of reduced eGFR. Cystatin C mRNA is expressed in subcutaneous and omental adipose tissue, at twice higher levels in nonadipose than in adipose cells. Gene expression and cystatin C release by adipose tissue explants increase two‐ to threefold in obesity. These data confirm elevation of serum cystatin C in human obesity and strongly argue for a contribution of increased production of cystatin C by enlarged adipose tissue. Because cystatin C has the potential to affect adipose tissue and vascular homeostasis through local and/or systemic inhibition of cathepsins, this study adds a new factor to the list of adipose tissue secreted bioactive molecules implicated in obesity and obesity‐linked complications.

Abstract-Thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described fibrinolysis inhibitor that circulates in plasma as a procarboxypeptidase and is converted into an active form during coagulation. The physiological relevance of TAFI is not known, but it might be involved in pathways regulating fibrin deposition. Our aim was to determine the interindividual variability of plasma TAFI antigen values and their associations with conventional cardiovascular risk factors. Six hundred twenty-six consecutive patients (277 men) attending a metabolic ward for primary prevention were studied. TAFI antigen presented a large range of values, with a 2-to 3-fold increase between the 10th and 90th percentiles. No difference was observed between the 2 sexes. A significant correlation was observed between age and TAFI levels in women only. After adjustment for age, TAFI antigen was positively correlated in men for the waist-to-hip circumference ratio and blood pressure, whereas no significant correlation was observed in women. Stepwise multiple linear regression analysis indicated a low contribution of the parameters studied to the variability of TAFI antigen levels; the waist-to-hip circumference ratio accounted for only 2% in men, and age accounted for only 3% in women. Results were compared with those of fibrinogen and plasminogen activator inhibitor-1; cardiovascular risk factors in men and women accounted for 16% and 9.5%, respectively, of the fibrinogen variance and 36% and 32%, respectively, of the plasminogen activator inhibitor-1 variance. These observations did not attribute an important role to lifestyle characteristics in the control of TAFI antigen concentration in plasma. Because of the large interindividual variability of TAFI levels in plasma, genetic control may be involved. Key Words: thrombin-activatable fibrinolysis inhibitor Ⅲ cardiovascular risk Ⅲ fibrinogen Ⅲ plasminogen activator inhibitor-1

SummaryFree-TFPI (f-TFPI) presents high anticoagulant activity and its plasma level correlates with unfavorable outcomes in unstable angina. Total TFPI (t-TFPI) represents mainly the lipid-bound form which seems to have a poor anticoagulant activity. Until now, it is not known whether the variations of f-TFPI plasma levels are determined by environmental factors. The aim of our study was to evaluate the influence of cardiovascular risk factors on plasma levels of f-TFPI and relations with other endothelial derived molecules in a population of 626 patients (277 men and 349 women) attending a metabolic ward for primary prevention of coronary disease.Free and total TFPI plasma levels were poorly correlated. f-TFPI levels increased with age in both sexes, t-TFPI in women only. Ageadjusted correlations of TFPI levels with conventional cardiovascular risk factors and endothelial cell markers showed different patterns for f-TFPI and t-TFPI. f-TFPI correlated with parameters associated with insulin resistance, particularly in females. f-TFPI was also positively associated in both genders with fibrinogen and endothelial cell markers: t-PA, thrombomodulin (TM) and von Willebrand factor (vWF). t-TFPI correlated strongly with LDL-C in both sexes. It also correlated negatively with parameters of the insulin resistance syndrome. t-TFPI also correlated with TM but not with other endothelial cell markers. The results of the multivariate step by step analysis showed that cardiovascular risk factors poorly explained the f-TFPI variability (7% and 4% in men and women, respectively), whereas they explained 16 and 20% of t-TFPI variability in men and women respectively (mostly related to LDL-C).In conclusion, this study showed that free- and total-TFPI are regulated differently. f-TFPI strongly correlates with endothelial cell markers and t-TFPI is more related to conventional cardiovascular risk factors. The strong gender effect on f-TFPI levels remains to be explained.