Resistin,Adiponectin, Ghrelin,Leptin, and Proinflammatory Cytokines: Relationships in Obesity

Objective: To evaluate interactions among leptin, adiponectin, resistin, ghrelin, and proinflammatory cytokines [tumor necrosis factor receptors (TNFRs), interleukin‐6 (IL‐6)] in nonmorbid and morbid obesity. Research Methods and Procedures: We measured these hormones by immunoenzyme or radiometric assays in 117 nonmorbid and 57 morbidly obese patients, and in a subgroup of 34 morbidly obese patients before and 6 months after gastric bypass surgery. Insulin resistance by homeostasis model assessment, lipid profile, and anthropometrical measurements were also performed in all patients. Results: Average plasma lipids in morbidly obese patients were elevated. IL‐6, leptin, adiponectin, and resistin were increased and ghrelin was decreased in morbidly obese compared with nonmorbidly obese subjects. After adjusting for age, gender, and BMI in nonmorbidly obese, adiponectin was positively associated with HDLc and gender and negatively with weight (β = ?0.38, p < 0.001). Leptin and resistin correlated positively with soluble tumor necrosis factor receptor (sTNFR) 1 (β = 0.24, p = 0.01 and β = 0.28, p = 0.007). In the morbidly obese patients, resistin and ghrelin were positively associated with sTNFR2 (β = 0.39, p = 0.008 and β = 0.39, p = 0.01). In the surgically treated morbidly obese group, body weight decreased significantly and was best predicted by resistin concentrations before surgery (β = 0.45, p = 0.024). Plasma lipids, insulin resistance, leptin, sTNFR1, and IL‐6 decreased and adiponectin and ghrelin increased significantly. Insulin resistance improved after weight loss and correlated with high adiponectin levels. Discussion: TNFα receptors were involved in the regulatory endocrine system of body adiposity independently of leptin and resistin axis in nonmorbidly obese patients. Our results suggest coordinated roles of adiponectin, resistin, and ghrelin in the modulation of the obesity proinflammatory environment and that resistin levels before surgery treatment are predictive of the extent of weight loss after bypass surgery.     

The Effect of Iron Treatment on Adhesion Molecules in Patients with Iron Deficiency Anemia

The present study was aimed to determine the effect of iron supplementation on levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in patients with iron deficiency anemia (IDA). In this study, 26 female patients diagnosed with iron deficiency were treated approximately 3 months of oral iron supplementation (99 ± 10 days; ferrous glycine sulfate; 100 mg/day of elemental iron). Levels of sICAM-1 and sVCAM-1 were assessed prior to treatment and after approximately 3 months of treatment and compared with 26 healthy female subjects. A significant increase in sVCAM levels was found in the patients with iron deficiency at the end of the treatment relative to pretreatment levels compared to controls, whereas no significant differences were determined in sICAM levels. In the posttreatment period, no significant change was observed in sICAM levels compared to the pretreatment levels, whereas sVCAM levels decreased. However, after the treatment period, the sVCAM, hemoglobin, mean corpuscular volume (MCV), and serum ferritin levels did not return to the normal range compared to the controls. Pretreatment sVCAM-1 levels were inversely correlated with levels of hemoglobin, hemotocrit, MCV, serum iron, and ferritin. After treatment, the sVCAM-1 levels were negatively correlated with ferritin levels. Levels of sVCAM were significantly higher in patients with IDA than controls. After the treatment period, the sVCAM levels were not completely normalized in patients with IDA compared to controls, regardless of the presence of inadequate levels of hemoglobin, MCV, and serum ferritin. Thus, iron supplementation not only ameliorates anemia, but may also reduce the inflammation markers in cases with IDA.     

Soluble intercellular adhesion molecules, soluble vascular cell adhesion molecules, and risk of coronary heart disease

Objective: We examined the association of circulating levels of soluble intercellular adhesion molecules (sICAM‐1) and soluble vascular cell adhesion molecules (sVCAM‐1) with coronary heart disease (CHD) risk factors and whether the adhesion molecules alone, and in combination, can serve as predictors of coronary CHD. Research Methods and Procedures: Among 18,225 men from the Health Professional Follow‐up Study who provided blood in 1994, we documented 266 incidents of non‐fatal myocardial infarction or fatal CHD during 6 years of follow‐up. The cases were matched 1:2 with non‐cases on age, smoking, and month of blood draw. We found both adhesion molecules directly associated with BMI, inflammatory biomarkers, and triglycerides and inversely associated with high‐density lipoprotein and alcohol intake (p < 0.05). After adjustment for C‐reactive protein, cholesterol‐to‐high‐density lipoprotein ratio, age, smoking, BMI, physical activity, alcohol intake, history of diabetes, parental history of CHD, aspirin use, antihypertensive drug use, and fasting status, the relative risk of CHD was 1.69 [95% confidence interval (CI), 1.14 to 2.51] for sICAM‐1 and 1.34 (95% CI, 0.91 to 1.96) for sVCAM‐1, when comparing the top quintile with the lower four quintiles. Control for other inflammatory or lipid biomarkers did not appreciably attenuate the associations. When we cross‐classified participants based on their sICAM‐1 and sVCAM‐1 levels, only the men in the top quintile of both biomarkers [relative risk = 2.39 (95% CI, 1.45 to 3.91)] had a significantly elevated risk of CHD (P interaction = 0.01, multivariate model). Discussion: sICAM‐1 and sVCAM‐1 are directly associated with obesity and other CHD risk factors. The combination of high levels of both adhesion molecules might be associated with the development of CHD, independent of other CHD risk factors.     

HMGB1 contributes to glomerular endothelial cell injury in ANCA‐associated vasculitis through enhancing endothelium–neutrophil interactions

Our previous studies demonstrated that high mobility group box‐1 (HMGB1), a typical damage‐associated molecular pattern (DAMP) protein, is associated with the disease activity of antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV). Moreover, HMGB1 participates in ANCA‐induced neutrophil activation. The current study aimed to investigate whether HMGB1 regulated the interaction between neutrophils and glomerular endothelial cells (GEnC) in the presence of ANCA. Correlation analysis on HMGB1 levels in AAV patients and soluble intercellular cell adhesion molecule‐1 (sICAM‐1) levels or vascular endothelial growth factor (VEGF) levels, which are markers of endothelial cell activation, was performed. The effect of HMGB1 on neutrophil migration towards GEnC, respiratory burst and degranulation of neutrophils in coculture conditions with GEnC was measured. The activation of neutrophils, the activation and injury of GEnC, and the consequent pathogenic role of injured GEnC were evaluated. Plasma levels of HMGB1 correlated with sICAM‐1 and VEGF (r = 0.73, P < 0.01; r = 0.41, P = 0.04) in AAV patients. HMGB1 increased neutrophil migration towards GEnC, as well as respiratory burst and degranulation of neutrophils in the presence of ANCA in the coculture system. In the presence of robust neutrophil activation, GEnC were further activated and injured in the coculture system of GEnC and neutrophils. In addition, injured GEnC could produce TF‐positive leuco‐endothelial microparticles and endothelin‐1 (ET‐1), while NF‐κB was phosphorylated (S529) in the injured GEnC. Plasma levels of HMGB1 correlated with endothelial cell activation in AAV patients. HMGB1 amplified neutrophil activation and the activation and injury of GEnC in the presence of ANCA.     

Improved Arteriole‐to‐Venule Ratio of Retinal Vessels Resulting From Bariatric Surgery

Obesity causes increased morbidity and mortality from metabolic and cardiovascular disease (CVD). We investigated the effect of bariatric surgery on endothelial dysfunction (ED) in retinal vessels as a marker of metabolic and cardiovascular risk in patients with obesity WHO III. Thirty consecutive patients (19/11, w/m) were evaluated by anthropometry, lipid profile, and oral glucose tolerance test before and after bariatric surgery (Mannheim Obesity Study (MOS); NCT 00770276). Risk stratification was performed by the presence of metabolic syndrome (MetS) according to ATP‐III (adult treatment panel‐III). Subclinical atherosclerosis was assessed by measurement of intima‐media thickness (IMT). Flicker light response of retinal vessels was used as measures of ED. We measured their arteriole‐to‐venule ratio (AVR) for evaluation of vascular pathology. After a median of 9 months following bariatric surgery, mean weight loss was 39.4 kg (37.3%). Remission of impaired glucose metabolism was achieved in 53.3% of affected patients. Dyslipidemia improved significantly (triglycerides ?61.3 mg/dl, P < 0.0001, total cholesterol ?28.2 mg/dl, P = 0.002, and low‐density lipoprotein cholesterol were reduced ?24.5 mg/dl, P = 0.008). This resulted in a significant reduction of patients classified for MetS (27 vs. 9, P < 0.0001). Adiponectin increased by 2.08 µg/l (P = 0.032) and high sensitivity C‐reactive protein (hs‐CRP) and soluble intercellular cell adhesion molecule (sICAM) decreased (?7.3 mg/l, P < 0.0001 and ?146.4 ng/ml, P = 0.0006). AVR improved significantly (+0.04, P < 0.0001), but neither Flicker light response nor IMT changed significantly. Retinal AVR is ameliorated after bariatric intervention. As an increased AVR results from either or both widening retinal arteriolar caliber and narrowing retinal venular caliber, an improvement in small vessel profile is evident 9 months after bariatric surgery.     

Improvement of Insulin Resistance and Early Atherosclerosis in Patients after Gastric Banding

Objective: To evaluate the effect of massive weight loss on insulin sensitivity, soluble adhesion molecules, and markers of the insulin resistance syndrome (IRS). Research Methods and Procedures: Eighteen morbidly obese patients underwent gastric banding and were evaluated before and 6 and 12 months after surgery. Total insulin secretion, hepatic insulin extraction, and insulin sensitivity were analyzed by oral glucose‐tolerance test model analysis. In addition, soluble intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, E‐selectin, leptin, high‐sensitivity C‐reactive protein, plasminogen activating factor‐1 (PAI‐1), and tissue plasminogen activator were measured. Results: BMI dropped from 45.22 ± 5.62 to 36.99 ± 4.34 kg/m² after 6 months and 33.72 ± 5.55 kg/m² after 12 months (both p < 0.0001). This intervention resulted in a significant reduction of blood pressure (p < 0.00001), triglycerides (p < 0.01), fasting blood glucose (p = 0.03), basal insulin (p < 0.001), and basal C‐peptide (p = 0.008) levels. Total insulin secretion decreased (p < 0.05), whereas hepatic insulin extraction (p < 0.05) and oral glucose insulin sensitivity index (p < 0.0001) increased compared with baseline. Leptin (p < 0.0001) and E‐selectin levels decreased significantly after 6 and 12 months (p = 0.05), whereas significantly lower levels of intercellular adhesion molecule‐1 and PAI‐1 were only seen after 6 months. Subclinical inflammation, measured by high‐sensitivity C‐reactive protein, was lowered to normal ranges. No changes were observed in vascular cell adhesion molecule‐1 and tissue plasminogen activator levels. Discussion: Although gastric banding ameliorates several features of the IRS, including 29.05% improvement in insulin sensitivity and blood pressure and reduction of soluble adhesion molecules and PAI‐1, considerable weight loss did not normalize all components of the IRS in morbidly obese patients.     

Effect of Weight Loss on High‐Molecular Weight Adiponectin in Obese Children

Our aim was to determine the influence of weight reduction on total (T‐) and high‐molecular weight (HMW‐) adiponectin in obese (OB) prepubertal children. Seventy OB prepubertal white patients were followed for 18 months and studied after reducing their BMI by 1 (n = 51) and 2 standard deviation scores (SDS) (n = 21) under conservative treatment, and 6 months after achieving weight loss (n = 44). Body composition dual‐energy X‐ray absorptiometry (DXA) and serum levels of T‐ and HMW‐adiponectin, resistin, leptin, leptin soluble receptor (sOB‐R), tumoral necrosis factor‐α and interleukin‐6 were determined. The control group consisted of 61 healthy prepubertal children. At diagnosis T‐adiponectin was higher (P < 0.01; confidence interval (+0.04) — (+0.15)) and HMW‐adiponectin lower (P < 0.001; confidence interval (?0.45) ? (?0.21)) in OB children than in controls. A reduction in body fat increased T‐ and HMW‐adiponectin and sOB‐R (all P < 0.001) and decreased leptin (P < 0.001) and interleukin‐6 levels (P < 0.05). After 6 months of sustained weight reduction a decrease in tumoral necrosis factor‐α (P < 0.01) occurred, whereas weight recovery increased leptin (P < 0.001) and decreased T‐adiponectin (P < 0.05). HMW‐adiponectin levels negatively correlated with homeostasis model assessment (HOMA) index and BMI in the whole cohort (both P < 0.001), as did T‐adiponectin levels and HOMA index in OB patients (P < 0.01), but neither T‐ nor HMW‐adiponectin correlated with body fat content (BFC) in OB children. We conclude that the impairment of T‐ and HMW‐adiponectin levels in childhood obesity is different to that in elder OB patients, showing closer relationship with carbohydrate metabolism parameters than with BFC, but increasing their levels after weight loss and in association with metabolic improvement.     

Sexual Dimorphism and Regulation of Resistin,Adiponectin, and Leptin Expression in the Mouse

Objective: To examine gender differences and hormonal regulation of resistin, adiponectin, and leptin. Research Methods and Procedures: Plasma levels were measured, and mRNA expression in perigonadal fat was quantified by RNase protection assays. Results: Plasma resistin declined with age despite an increase in adiposity in both genders. In male mice, plasma leptin increased, whereas adiponectin levels were constant. In females, both adiponectin and leptin levels increased with age. Resistin mRNA levels were significantly higher in female than male mice at all ages, whereas leptin and adiponectin mRNA levels were similar in fat from 6‐week‐old male and female mice, and sexual dimorphism was apparent only in the older mice, with higher levels apparent in females. Castration did not abolish gender differences in plasma levels or resistin, adiponectin, or leptin mRNAs. Castration of male mice did not significantly change adipokine mRNA levels or plasma levels of resistin or leptin; however, adiponectin was significantly increased. Dihydrotestosterone treatment had no effect on adipokine mRNA expression or resistin and adiponectin levels but increased leptin levels. In contrast, ovariectomy significantly increased resistin mRNA abundance and decreased leptin and adiponectin mRNAs. Plasma leptin levels were also increased by ovariectomy, whereas resistin and adiponectin levels were unchanged. Estrogen replacement significantly reduced resistin mRNA and increased leptin and adiponectin mRNA levels but had no effect on plasma adipokine levels. Discussion: The gender differences in adipokine mRNA expression and plasma levels were not ablated by castration and seem to be dependent on other factors in addition to gonadal steroids.     

Long‐term effects of weight loss after bariatric surgery on functional and structural markers of atherosclerosis

Objective: Pronounced weight loss after bariatric surgery was demonstrated to have significant beneficial effects on surrogates of early atherosclerosis. The aim of this prospective examination was to investigate whether these improvements of endothelial function and vascular structure are persistent in the long‐term. Design and Methods: A total of 52 obese adults were examined before and 5 years after bariatric surgery. Carotid intima media thickness (IMT), brachial flow‐mediated dilation (FMD), abdominal fat distribution, and metabolic parameters were determined. Additional 18 months data were available from 27 patients. Results: After 5 years, mean weight loss ± SD of 25% ± 12 in all subjects was accompanied by known improvements in metabolism. Change in IMT was ?0.02 mm ± 0.007, whereas FMD improved by +1.5% ± 0.5. In the subgroup IMT decreased by 0.04 mm ± 0.06 within the first 18 months, whereas no significant change was observed between 18 month and 5 years. FMD improved by 3.8% ± 0.6 after 18 months followed by a nonsignificant decrease of ?1.4% ± 0.9. Conclusions: These long‐term results demonstrate that bariatric surgery‐induced weight loss improves both functional and structural markers of early atherosclerosis providing further evidence for the beneficial effects of weight loss on obesity‐associated alterations of the vasculature.     

Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

The role of exosomes derived from endothelial cells (ECs) in the progression of atherosclerosis (AS) and inflammation remains largely unexplored. We aimed to investigate whether exosome derived from CD137‐modified ECs (CD137‐Exo) played a major role in AS and to elucidate the potential mechanism underlying the inflammatory effect. Exosomes derived from mouse brain microvascular ECs treated with agonist anti‐CD137 antibody were used to explore the effect of CD137 signalling in AS and inflammation in vitro and vivo. CD137‐Exo efficiently induced the progression of AS in ApoE^?/? mice. CD137‐Exo increased the proportion of Th17 cells both in vitro and vivo. The IL‐6 contained in CD137‐Exo which is regulated by Akt and NF‐КB pathway was verified to activate Th17 cell differentiation. IL‐17 increased apoptosis, inhibited cell viability and improved lactate dehydrogenase (LDH) release in ECs subjected to inflammation induced by lipopolysaccharide (LPS). The expression of soluble intercellular adhesion molecule1 (sICAM‐1), monocyte chemoattractant protein‐1 (MCP‐1) and E‐selectin in the supernatants of ECs after IL‐17 treatment was dramatically increased. CD137‐Exo promoted the progression of AS and Th17 cell differentiation via NF‐КB pathway mediated IL‐6 expression. This finding provided a potential method to prevent local and peripheral inflammation in AS.     

Adipocyte Fatty Acid‐binding Protein as a Determinant of Insulin Sensitivity in Morbid‐obese Women

The aim of the study was to evaluate human plasma circulating levels of adipocyte fatty acid‐binding protein (A‐FABP) and its relationship with proinflammatory adipocytokines and insulin resistance in a severely obese cohort, before and 1 year after a surgical gastric bypass. Plasmatic levels of A‐FABP were measured in 77 morbid‐obese women before and 1 year after bariatric surgery. Anthropometrical parameters and body composition by bioelectrical impedance analysis were determined. Circulating levels of soluble tumor necrosis factor receptor 2 (sTNFR2), Interleukin 18 (IL‐18), adiponectin, and high‐sensitive C‐reactive protein (hsCRP) were also analyzed. Insulin resistance by homeostasis model assessment of insulin resistance (HOMA‐IR) index was calculated. After massive weight loss, A‐FABP plasmatic levels decreased significantly [7.6 (8.9) vs. 4.3 (5.1); P < 0,001] but no association with circulating adipokines or proinflammatory cytokines, both at the beginning and at the end of follow‐up, was observed. A decrease in sTNFR2, IL‐18, hsCRP, and an increase in adiponectin levels (P < 0.001 in all cases) were observed after the gastric bypass. HOMA‐IR index improved 1 year after surgery and after multiple regression analysis remained associated with A‐FABP after controlling for confounding variables (β = 0.322, P = 0.014; R² for the model 0.281). In morbid‐obese women, plasma A‐FABP concentrations were dramatically reduced after gastric bypass surgery. After weight loss this protein contributed to HOMA‐IR index independently of proinflammatory/antinflammatory cytokine profile. Further studies are warranted to elucidate the role of A‐FABP in the pathogenesis of insulin resistance in morbid obesity.     

The effect of pheochromocytoma treatment on subclinical inflammation and endocrine function of adipose tissue

The aim of our study was to evaluate the influence of surgical removal of pheochromocytoma on the endocrine function of adipose tissue and subclinical inflammation as measured by circulating C-reactive protein (CRP) levels. Eighteen patients with newly diagnosed pheochromocytoma were included into study. Anthropometric measures, biochemical parameters, serum CRP, leptin, adiponectin and resistin levels were measured at the time of diagnosis and six months after surgical removal of pheochromocytoma. Surgical removal of pheochromocytoma significantly increased body weight, decreased both systolic and diastolic blood pressure, fasting blood glucose and glycated hemoglobin levels. Serum CRP levels were decreased by 50 % six months after surgical removal of pheochromocytoma (0.49+/-0.12 vs. 0.23+/-0.05 mg/l, p<0.05) despite a significant increase in body weight. Serum leptin, adiponectin and resistin levels were not affected by the surgery. We conclude that increased body weight in patients after surgical removal of pheochromocytoma is accompanied by an attenuation of subclinical inflammation probably due to catecholamine normalization. We failed to demonstrate an involvement of the changes in circulating leptin, adiponectin or resistin levels in this process.     

Serum amyloid A: a marker of adiposity-induced low-grade inflammation but not of metabolic status

Objective: Adipocytes secrete a series of acute phase proteins including serum amyloid A (SAA); the link with metabolic status is unknown. We studied the variations of expression of the SAA gene in adipose and liver tissues and of SAA serum levels, as well as their relationships with metabolic features during weight loss. Research Methods and Procedures: Plasmatic variations of SAA, inflammatory markers (high sensitivity C‐reactive protein, interleukin‐6, fibrinogen, and orosomucoid), and adipokines (adiponectin, leptin) were studied in 60 morbidly obese patients before and after gastric surgery. For 10 subjects, SAA mRNA expression was measured at baseline in subcutaneous white adipose tissue (scWAT) and visceral white adipose tissue (vWAT) and in the liver. The evolution of SAA mRNA expression was also studied after surgery in scWAT. Results: SAA serum concentration displayed a significant reduction 3 months after surgery and remained stable beyond 6 months. mRNA expression of inducible SAA isoforms (SAA 1 and 2) in scWAT was higher than in vWAT (p = 0.01) and the liver (p < 0.01) and correlated significantly with BMI, SAA, and high sensitivity C‐reactive protein serum concentrations but not with metabolic markers (glucose, insulin, lipid parameters, adiponectin). SAA serum level and its variation during weight loss significantly correlated with adiposity markers (BMI and adipocyte volume, p < 0.01) and inflammatory markers but not with variations of metabolic parameters. The variations of SAA expression in scWAT after surgery correlated with changes in BMI and SAA protein serum levels (p < 0.05). Discussion: SAA can be considered as a marker of adiposity‐induced low‐grade inflammation but not of the metabolic status of obese subjects.     

Troglitazone‐Induced Changes in Adiponectin Do Not Affect Endothelial Function in Diabetes

Objective: Adiponectin has been proposed to be related to endothelial function. We have examined the relationship between the increase in adiponectin levels that is associated with troglitazone treatment and endothelium‐dependent vasodilation in type 2 diabetic patients. Research Methods and Procedures: Seventy‐two patients participated in this randomized, placebo‐controlled, double‐blinded study. High‐resolution ultrasound images were used to measure the flow‐mediated dilation (endothelium‐dependent) and nitroglycerin‐induced dilation (endothelium‐independent) of the brachial artery. Laser Doppler perfusion imaging was employed to measure the vascular reactivity in the forearm skin. Results: Troglitazone treatment resulted in an average 75% increase in the adiponectin levels, but no changes were observed in the endothelium‐dependent vasodilation, any other measurement of vascular reactivity, or any other markers of endothelial activation. Also, no changes were observed in the expression of the receptor for advanced glycation end‐products in skin biopsies taken from the forearm. Significant correlations were observed during troglitazone treatment between the changes in the adiponectin levels and the changes in fasting plasma glucose (r = ?0.29, p < 0.05), hemoglobin A_1c (r = ?0.30, p < 0.05), total cholesterol (r = 0.25, p < 0.05), and low‐density lipoprotein‐cholesterol (r = 0.34, p < 0.01). Discussion: The increase in adiponectin levels after troglitazone treatment is not associated with an improvement in the endothelium‐dependent vasodilation, indicating that adiponectin is not a major determinant of endothelial function. In addition, receptor for advanced glycation end‐products expression in the skin microcirculation is not affected by troglitazone treatment.     

Sphingosine‐1‐phosphate (S1P) enhances glomerular endothelial cells activation mediated by anti‐myeloperoxidase antibody‐positive IgG

Cumulating evidences suggested an important role of sphingosine‐1‐phosphate (S1P) and its receptors in regulating endothelial barrier integrity. Our previous study revealed that the circulating S1P levels and renal expression of S1PRs correlated with disease activity and renal damage in patients with antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV). This study investigated the role of S1P and its receptors in myeloperoxidase (MPO)‐ANCA‐positive IgG‐mediated glomerular endothelial cell (GEnC) activation. The effect of S1P on morphological alteration of GEnCs in the presence of MPO‐ANCA‐positive IgG was observed. Permeability assay was performed to determine endothelial monolayer activation in quantity. Both membrane‐bound and soluble ICAM‐1 and VCAM‐1 levels were measured. Furthermore, antagonists and/or agonists of various S1PRs were employed to determine the role of different S1PRs. S1P enhanced MPO‐ANCA‐positive IgG‐induced disruption of tight junction and disorganization of cytoskeleton in GEnCs. S1P induced further increase in monolayer permeability of GEnC monolayers in the presence of MPO‐ANCA‐positive IgG. S1P enhanced MPO‐ANCA‐positive IgG‐induced membrane‐bound and soluble ICAM‐1/VCAM‐1 up‐regulation of GEnCs. Soluble ICAM‐1 levels in the supernatants of GEnCs stimulated by S1P and MPO‐ANCA‐positive IgG increased upon pre‐incubation of S1PR1 antagonist, while pre‐incubation of GEnCs with the S1PR1 agonist down‐regulated sICAM‐1 level. Blocking S1PR2‐4 reduced sICAM‐1 levels in the supernatants of GEnCs stimulated by S1P and MPO‐ANCA‐positive IgG. Pre‐incubation with S1PR5 agonist could increase sICAM‐1 level in the supernatants of GEnC stimulated by S1P and MPO‐ANCA‐positive IgG. S1P can enhance MPO‐ANCA‐positive IgG‐mediated GEnC activation through S1PR2‐5.     

Effect of PPAR-gamma agonist treatment on markers of endothelial dysfunction in patients with type 2 diabetes mellitus

Thiazolidinediones are insulin-sensitizing drugs acting through peroxisome proliferator-activated receptor (PPAR)-gamma. The aim of our study was to evaluate the effect of 5-month treatment with PPAR-gamma agonist--rosiglitazone (4 mg/day), on the circulating markers of endothelial dysfunction and to evaluate the role of changes in endocrine function of adipose tissue in this process. Biochemical and metabolic parameters, circulating adiponectin, resistin, ICAM-1, VCAM-1, E-selectin, P-selectin, PAI-1, myeloperoxidase (MPO), and matrix metalloproteinase-9 (MMP-9) concentrations were assessed in 10 women with type 2 DM before and after rosiglitazone treatment and in a control group of healthy women. At baseline, diabetic group had significantly higher serum concentrations of glucose, glycated hemoglobin, V-CAM and PAI-1 compared to control group. Adiponectin levels tended to be lower in diabetic group, while resistin concentrations did not differ from control group. Rosiglitazone treatment improved diabetes compensation, significantly reduced VCAM-1, PAI-1 and E-selectin concentrations and increased adiponectin levels, while it did not affect serum resistin concentrations. Adiponectin concentrations at baseline were inversely related to E-selectin and MPO levels, this correlation disappeared after rosiglitazone treatment. We conclude that 5-month rosiglitazone treatment significantly reduced several markers of endothelial dysfunction. This effect could be at least in part attributable to marked increase of circulating adiponectin levels.     

Benefits of Regular Exercise on Inflammatory and Cardiovascular Risk Markers in Normal Weight,Overweight and Obese Adults

Obesity is a worldwide epidemic that increases the risk of several well-known co-morbidities. There is a complicated relationship between adipokines and low-grade inflammation in obesity and cardiovascular disease (CVD). Physical activity practices have beneficial health effects on obesity and related disorders such as hypertension and dyslipidemia. We investigated the effects of 6 and 12 months of moderate physical training on the levels of adipokines and CVD markers in normal weight, overweight and obese volunteers. The 143 participants were followed up at baseline and after six and twelfth months of moderate regular exercise, 2 times a week, for 12 months. The volunteers were distributed into 3 groups: Normal Weight Group (NWG,), Overweight Group (OVG) and Obese Group (OBG). We evaluated blood pressure, resting heart rate, anthropometric parameters, body composition, fitness capacity (VO_2max and isometric back strength), cardiovascular markers (CRP, total cholesterol, LDL-c, HDL-c, homocysteine) and adipokine levels (leptin, adiponectin, resistin, IL-6 and TNF-alpha). There were no significant changes in anthropometric parameters and body composition in any of the groups following 6 and 12 months of exercise training. Leptin, IL-6 levels and systolic blood pressure were significantly elevated in OBG before the training. Regular exercise decreased HDL-c, leptin, adiponectin and resistin levels and diastolic blood pressure in OVG. In OBG, exercise diminished HDL-c, homocysteine, leptin, resistin, IL-6, adiponectin. Moderate exercise had no effect on the body composition; however, exercise did promote beneficial effects on the low-grade inflammatory state and CVD clinical markers in overweight and obese individuals.     

The influence of very-low-calorie-diet on serum leptin, soluble leptin receptor, adiponectin and resistin levels in obese women

The aim of our study was to determine whether adipocyte-derived hormones leptin, adiponectin and resistin contribute to the improvement of insulin sensitivity after very-low calorie diet (VLCD). Therefore, serum levels of these hormones were measured in fourteen obese females before and after three weeks VLCD and in seventeen age- and sex-matched healthy controls. Body mass index, HOMA index, serum insulin and leptin levels in obese women before VLCD were significantly higher than in control group (BMI 48.01+/-2.02 vs. 21.38+/-0.42 kg/m(2), HOMA 10.72+/-2.03 vs. 4.69+/-0.42, insulin 38.63+/-5.10 vs. 18.76+/-1.90 microIU/ml, leptin 77.87+/-8.98 vs. 8.82+/-1.52 ng/ml). In contrast, serum adiponectin and soluble leptin receptors levels were significantly lower in obese women before VLCD than in the control group. No differences were found in serum glucose and resistin levels between the obese group before VLCD and the control group. VLCD significantly decreased BMI, HOMA index, serum glucose, insulin and leptin levels and increased soluble leptin receptor levels. The changes in serum adiponectin and resistin levels in obese women after VLCD did not reach statistical significance. We conclude that leptin and soluble leptin receptor levels were affected by VLCD while adiponectin and resistin concentrations were not. Therefore, other mechanisms rather than changes in the endocrine function of the adipose tissue are probably involved in the VLCD-induced improvement of insulin sensitivity.