Search

Background: Cardiovascular (CV) morbidity, mortality, and metabolic syndrome are associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Here, lipids and other metabolic markers in relation to vascular function and clinical markers were evaluated in RA and AS patients undergoing one-year anti-TNF therapy., Patients and Methods: Fifty-three patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Various lipids, paraoxonase (PON) and arylesterase (ARE) activities, myeloperoxidase (MPO) and adipokine levels were determined overtime. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation., Results: Anti-TNF therapy decreased ARE activity, MPO, adiponectin, and chemerin levels after 12 months ( p < 0.05). Lipids, PON activity, and leptin remained unchanged. Regression analyses suggested variable associations of IMT, PWV, and FMD with ARE, MPO, leptin, and lipids ( p < 0.05). On the other hand, these metabolic parameters were significantly associated with disease duration, CV history, CRP, obesity, PWV, and IMT ( p < 0.05). One-year anti-TNF treatment together with baseline leptin ( p = 0.039) or CRP ( p = 0.016) levels determined 12 months of lipid changes overtime. TNF inhibition together with baseline disease activity determined ARE activity changes ( p = 0.046). Anti-TNF therapy and baseline chemerin levels determined IMT changes overtime ( p = 0.003)., Conclusions: Assessment of various metabolic parameters together with disease activity, CRP, and ultrasound-based techniques may exert additional value in determining CV burden and in monitoring the effects of biologics on preclinical vascular pathophysiology.

Background: Obestatin is a ghrelin-associated peptide, derived from preproghrelin. Although many of its effects are unclear, accumulating evidence supports positive actions on both metabolism and cardiovascular function. To date, level of obestatin and its correlations to the lipid subfractions in non-diabetic obese (NDO) patients have not been investigated., Methods: Fifty NDO patients (BMI: 41.96 ± 8.6 kg/m 2 ) and thirty-two normal-weight, age- and gender-matched healthy controls (BMI: 24.16 ± 3.3 kg/m 2 ) were enrolled into our study. Obestatin level was measured by ELISA. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions, intermediate density lipoprotein (IDL) and very low-density lipoprotein (VLDL) levels and mean LDL size were detected by nongradient polyacrylamide gel electrophoresis (Lipoprint)., Results: Serum level of obestatin was significantly lower in NDO patients compared to controls (3.01 ± 0.5 vs. 3.29 ± 0.6 μg/ml, p < 0.05). We found significant negative correlations between the level of obestatin and BMI (r = - 0.33; p < 0.001), level of serum glucose (r = - 0.27, p < 0.05), HbA1c (r = - 0.38; p < 0.001) and insulin (r = - 0.34; p < 0.05). Significant positive correlation was found between obestatin level and the levels of ApoA1 (r = 0.25; p < 0.05), large HDL subfraction ratio and level (r = 0.23; p < 0.05 and r = 0.24; p < 0.05), IDL (r = 0.25 p < 0.05) and mean LDL size (r = 0.25; p < 0.05). Serum VLDL ratio and level negatively correlated with obestatin (r = - 0.32; p < 0.01 and r = - 0.21; p = 0.05). In multiple regression analysis obestatin was predicted only by VLDL level., Conclusions: Based on our data, measurement of obestatin level in obesity may contribute to understand the interplay between gastrointestinal hormone secretion and metabolic alterations in obesity.

Background and Aims: Some crucial associations between obesity-related altered adipokine levels and the main factors of atherosclerotic, atherothrombotic processes are not fully known. We analysed the relationships of classic adipokines, namely leptin, resistin, adiponectin, tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) with the markers of platelet activation, including mean platelet volume (MPV), platelet surface/soluble P-selectin, platelet-derived microparticles (PMPs), the parameters of coagulation abnormalities and common carotid intima-media thickness (IMT) in obese patients with or without atherosclerotic comorbidities in comparison to age- and sex-matched controls., Methods and Results: We enrolled 154 obese individuals, including 98 suffering from atherosclerotic concomitant conditions, 56 free of atherosclerotic comorbidities and 62 healthy controls. Plasma levels of leptin, resistin, adiponectin, TNF-α, IL-6, soluble P-selectin, and plasminogen activator inhibitor-1 antigen (PAI-1 ag) were analysed by ELISA. Platelet surface P-selectin and PMPs were measured by flow cytometry. IMT was detected by ultrasonography. Adipokines were closely associated with markers of platelet hyperactivity, hypercoagulability, hypofibrinolysis and IMT. Significant independent associations were found between leptin and platelet count (p < 0.0001), MPV (p = 0.019), PMPs (p < 0.0001), fibrinogen (p = 0.001), factor VIII (FVIII) activity (p = 0.035); adiponectin and PAI-1 ag (p = 0.035); resistin and soluble P-selectin (p = 0.002); TNF-α and PAI-1 ag (p < 0.0001); and IL-6 and fibrinogen (p = 0.011). Finally, leptin (p = 0.0005), adiponectin (p = 0.019), IL-6 (p = 0.001), MPV (p = 0.0003), PMP (p = 0.008), and FVIII activity (p = 0.043) were independent predictors of IMT., Conclusion: Overall, we suggest that in obese subjects altered adipokine levels play a key role in common carotid atherosclerosis both directly and through haemostatic parameters., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Oxidative stress and chronic low-grade inflammation are major characteristics of obesity-related disorders. The dominance of pro-oxidant and pro-inflammatory mechanisms triggers insulin resistance and enhances the progression of atherosclerosis. Discovered first as an esterase that hydrolyze organophosphates, human paraoxonase-1 is bound to high-density lipoprotein and inhibits the oxidation of lipoproteins and reduces the degree of inflammation, hence it is considered to act against atherosclerosis. In contrast, the majority of the adipokines secreted from the enlarged white adipose tissue promote the atherosclerotic process; and altered adipokine secretion is now regarded as one of the major contributors of increased cardiovascular morbidity and mortality in obesity. In this review, we detail the correlations between paraoxonase-1 and some selected adipokines, namely leptin, adiponectin and chemerin. Adipokine imbalance leads to decreased paraoxonase-1 activity that results in enhanced atherosclerosis; therefore, altered adipokine secretion may be predictive of cardiovascular complications in obesity. As an active organ secreting biological active substances, white adipose tissue may also act as a "fine-tuner" of immune and endocrine actions attenuating or enhancing reactions triggered by pathogens, inflammation and metabolic stimuli; and obesity, as a chronic noxious state may perturb the proper functioning of this fine-tuning process. Further investigations are of major importance to elucidate the associations between adipokines and paraoxonase-1 and to establish accurate interventions against obesity-related disorders., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were shown to contribute to atherogenesis, while human paraoxonase-1 (PON1) protects against oxidative stress. Although several studies investigated these biomarkers, their associations have not been completely clarified yet. We aimed to investigate these parameters in overweight hyperlipidemic, lipid-lowering therapy-naive patients (n=167) with and without vascular complications., Design and Methods: MPO, MMP-9 and TIMP-1 levels were measured by ELISA. PON1 activities were detected spectrophotometrically. PON1 phenotype was calculated by using a dual substrate method., Results: Patients with vascular complications (VC) had significantly higher MPO and TIMP-1 levels compared to those without (patients with no vascular complications; NVC) (728 (367.25-1177.90) mg/ml vs. 315.9 (176.05-687.40) mg/ml; p<0.001; and 172.7 (157.7-197.7) ng/ml vs. 152.6 (129.3-172.3) ng/ml; p<0.0001; respectively). MPO levels showed a significant negative correlation with PON1 arylesterase activity (whole patient group (W): r=0.42, p<0.0001; VC: r=0.44, p=0.01; NVC: r=0.39, p<0.0001) and positive correlations with MMP-9 (W: r=0.37, p<0.0001; VC: r=0.29, p=0.07; NVC: r=0.42, p<0.0001) and TIMP-1 (W: r=0.42, p<0.0001; VC: r=0.33, p<0.05; NVC: r=0.41, p<0.0001), respectively. PON1 arylesterase activity was found to be an independent predictor of MPO levels in the whole patient group (β=-0.350, p<0.0001) or when studied separately in the subgroups with or without cardiovascular complications (VC: β=-0.57, p<0.05; NVC: β=-0.33, p<0.0001)., Conclusions: Our results suggest that parallel investigation of MPO, MMP-9 and TIMP-1 levels and PON1 arylesterase activity may be a more accurate indicator of atherosclerosis, which may allow earlier treatment and therefore, improvement of treatment efficacy., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Rheumatoid arthritis (RA), especially active disease, is associated with considerable changes in body composition, lipids, adipokines and insulin sensitivity. Metabolic changes, such as increased total cholesterol, LDL cholesterol and triglyceride levels, occur even in preclinical RA. Active RA is associated with decreased lipid levels, BMI, fat and muscle mass, as well as altered lipid profiles. Some of these changes are also seen in metabolic syndrome, and could increase cardiovascular mortality. Importantly, the systemic inflammation underlying RA is an independent risk factor for cardiovascular disease. This Perspectives article summarizes data on the associations of various components of metabolic syndrome with RA, and discusses the effects of biologic therapy on these factors. The authors propose that components of metabolic syndrome should be monitored in patients with RA throughout the disease course, and argue that optimal disease control using biologic agents might attenuate several adverse effects of metabolic syndrome in these patients.

The prevalence of obesity has been increasing worldwide. Chemerin is a recently discovered adipokine secreted by the enlarged adipose tissue with diverse biological effects that are not well detailed yet. This study aimed to elucidate the potential role of chemerin in oxidative stress and inflammation that are characteristics for excess weight and may eventually lead to insulin resistance and atherosclerotic complications. We also analysed the associations between chemerin and classical adipokines, namely leptin and adiponectin. Therefore, we investigated non-diabetic obese patients without manifest cardiovascular disease and compared their data to healthy lean individuals. Chemerin correlated positively with markers of oxidative stress and inflammation, while it showed a negative correlation with the measure of antioxidant status, characterized by the HDL-linked paraoxonase-1 enzyme. Chemerin also correlated positively with leptin and negatively with adiponectin respectively. In our study population, oxidized low-density lipoprotein and high-sensitivity C-reactive protein were found to be the strongest predictors of chemerin level. We conclude that chemerin may contribute to chronic inflammation and increased oxidative stress in obese individuals, even in the absence of manifest insulin resistance., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: The prevalence of obesity is increasing in adult and child populations throughout the world. Childhood obesity has a great impact on adult cardiovascular morbidity and mortality; treatment of this pathological state is important given the significant health consequences. We investigated the effect of short-term lifestyle changes on the alteration of human serum paraoxonase-1 (PON1) activities, leptin, adiponectin, E-selectin, and asymmetric dimethylarginine (ADMA) as atherogenic and antiatherogenic factors in obese children. PON1 protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low density lipoprotein (LDL) and therefore may protect against atherosclerosis., Methods: A total of 23 white obese and overweight children (age, 11.43 ± 1.78 years; 8 girls, 15 boys) participated in a 2-week-long lifestyle camp based on a diet and exercise program. Overweight and obesity were defined according to the national body mass index (BMI) reference tables for age and sex., Results: After a 2-week-long supervised diet and aerobic exercise program, obese children had significantly lower leptin (55.02 ± 33.42 ng/ml vs 25.37 ± 19.07 ng/ml; p < 0.0001), ADMA (0.68 ± 0.15 μmol/l vs 0.55 ± 0.16 μmol/l; p < 0.01), and E-selectin levels (67.19 ± 30.35 ng/ml vs 46.51 ± 18.40 ng/ml; p < 0.0001), whereas they had significantly higher PON1 paraoxonase activity (110.48 ± 72.92 U/l vs 121.75 ± 93.48 U/l; p < 0.05) besides the antiatherogenic alteration of the lipid profile and significant weight change (70.32 ± 19.51 kg vs 67.01 ± 18.75 kg, p < 0.0001; BMI, 28.95 ± 5.05 kg/m(2) vs 27.43 ± 4.82 kg/m(2), p < 0.0001). Adiponectin and PON1 arylesterase activity did not change significantly., Conclusions: Our investigation suggests that modifications in dietary habits and physical activity induce antiatherogenic changes in childhood obesity. These findings emphasize the major role of primary prevention and nonpharmaceutical treatment of childhood obesity through lifestyle changes based on diet and increased physical activity.

Childhood obesity is a predisposing factor for adult cardiovascular diseases. Human serum paraoxonase (PON1) may protect against atherosclerosis by hydrolyzing lipid peroxides in oxidized LDL. Alterations and potential correlations of PON1 activities, leptin and adiponectin levels in childhood obesity were studied. We measured PON1 paraoxonase and arylesterase activities, anthropometric parameters, leptin and adiponectin levels in 59 white, obese (obese group-OB: BMI corrected for age: 95.1 +/- 3.5 percentile, age: 11.9 +/- 1.6 y) and 51 normal-weight children (control group-C: BMI corrected for age: 64.1 +/- 8.4 percentile, age: 12.0 +/- 3.9 y). Obese children had significantly lower PON1 paraoxonase (OB: 84.80 (64.33/144.74) U/L versus. C: 99.42 (83.33/152.05) U/L; p < 0.05) and arylesterase activities (OB: 94.40 (82.20/108.70) U/L versus. C: 115.20 (93.70/126.00) U/L; p < 0.01), higher leptin (OB: 37.05 (24.33/53.87) ng/mL versus. C: 4.62 (2.52/17.6) ng/mL; p < 0.0001) and lower adiponectin levels (OB: 7.56 (5.69/12.06) microg/mL versus. C: 11.51 (8.84/14.49) microg/mL; p < 0.001) compared with the normal-weight group. PON1 arylesterase activity showed inverse univariate correlation with leptin (r = -0.29; p < 0.05) and positive correlation with adiponectin levels (r = 0.39; p < 0.01). In multiple regression analysis adiponectin was strongly associated with PON1 arylesterase activity in obese children (beta = 0.45, p < 0.02). Our results emphasize the importance of the investigated metabolic alterations which may have further effects on cardiovascular morbidity and mortality in later adulthood. Altered levels of leptin, adiponectin and PON1 activities may be useful markers beside the general risk factors in childhood obesity.

Obesity as a pathogenic disorder is a predisposing factor for cardiovascular diseases and shows an increasing incidence in the industrialized countries. Adipokines such as leptin, adiponectin and resistin have a great impact on the development of atherosclerosis in obesity. Elevated levels of leptin have been found to be atherogenic whereas decreased levels of adiponectin have been proved to be anti-atherogenic in recent studies. The exact role of resistin in the process of atherosclerosis has so far remained uncertain and controversial. In our recent work, we studied the alteration in human paraoxonase-1 (PON1) activity and adipokine levels; furthermore, we also aimed at identifying the potential correlation between these parameters in this metabolic disorder. We investigated the above-mentioned parameters both in adults and in children, with regard to the emerging role of childhood obesity and to get a clearer view of these factors during a whole lifetime. Investigating the adult population with a broad range of body mass index (BMI) we found significantly increased leptin and significantly decreased adiponectin and resistin levels and PON1 activity in the obese group compared to the lean controls. Adiponectin and resistin levels showed significantly positive correlation, while leptin and BMI showed significantly negative correlation with PON1 activity. Our findings were similar in childhood obesity: leptin showed significantly negative correlation, while adiponectin showed significantly positive correlation with PON1 activity. We found gender differences in the univariate correlations of leptin and adiponectin levels with PON1 activity in the adult population. In multiple regression analysis, adiponectin proved to be an independent factor of PON1 activity both in childhood and adult obesity, furthermore thiobarbituric acid-reactive substances (TBARS) also proved to be an independent predictor of the enzyme in adults, reflecting the important role of oxidative stress in obesity. Investigating PON 192 Q/R polymorphism by phenotypic distribution (A/B isoenzyme) in obese children, we found a significant correlation of PON1 arylesterase activity with leptin and adiponectin levels, and of body fat percentage with PON1 192 B isoenzyme. According to our studies, these metabolic changes in obesity predispose to the early development of atherosclerosis throughout our whole lifetime. Decreased activity of PON1 and alterations in adipokine levels in childhood obesity could contribute to an early commencement of this process, detected only later in adulthood by increased cardiovascular morbidity and mortality. Changed levels of leptin, adiponectin, resistin and PON1 activity at all ages, just like 192 Q/R polymorphism determined by phenotypic distribution, may be useful markers beside the general risk factors.

Unlabelled: Correlation of the plasma levels of insulin-sensitizing, anti-inflammatory and anti-atherosclerotic adiponectin with HDL has been demonstrated. However, its relation to HDL-bound paraoxonase 1 (PON1) has not been clarified. The association of serum PON1 activity with findings of metabolic syndrome was investigated in three age and sex-matched groups: (1) non-diabetic overweight subjects with BMI 28-39.9 kg/m(2) (n=25); (2) non-diabetic obese subjects with BMI>or=40 kg/m(2) (n=25); and (3) healthy, normal-weight controls (n=24). Of the parameters investigated, PON1 activity correlated positively with concentrations of HDL-C and adiponectin, and correlated negatively with BMI, waist circumference, systolic BP, levels of HbA(1C), and insulin, HOMA-IR, and TBARS. The positive correlation between adiponectin and PON1 remained significant even after adjustments for age, gender, BMI, blood pressure, HOMA-IR, HDL-C, LDL-C, and lipid peroxidation., Conclusions: PON1 activity shows negative association with markers of metabolic syndrome. We demonstrate that adiponectin is an independent variable of serum PON1, which may contribute to the anti-atherosclerotic effect of adiponectin.

Altered activities of high-density lipoprotein (HDL)-associated antioxidant enzyme paraoxonase 1 (PON1) and lipid transfer proteins, for example, cholesteryl ester transfer protein (CETP) and lecithin cholesterol acyltransferase (LCAT), participating in lipoprotein remodeling seem to play important roles in obesity-related accelerated atherosclerosis. Inverse associations of PON1 with obesity and serum leptin levels have been demonstrated. However, the relationship of leptin with CETP and LCAT in humans is less clear. Our aims were to investigate whether the elevated leptin level is (a) an independent predictor of low PON1 and (b) associated with alterations of CETP and LCAT activities. Seventy-four white subjects forming 3 age- and sex-matched groups were included into the study (groups 1 and 2: nondiabetic obese patients, n = 25 with body mass index [BMI] 28-39.9 kg/m2 and n = 25 with BMI >or=40 kg/m2, respectively; and group 3: 24 healthy, normal-weight control subjects). Paraoxonase 1 correlated inversely with BMI (r = -0.39, P < .01), waist circumferences (r = -0.42, P < .001), and leptin concentrations (r = -0.38, P < .001). However, in a multiple regression model, neither these variables nor others, for example, age, sex, blood pressure, insulin resistance (in homeostasis model assessment of insulin resistance [HOMA-IR]), HDL cholesterol, low-density lipoprotein cholesterol, or lipid peroxidation (measured as thiobarbituric acid reactive substances), proved to be independent predictors of PON1. Lecithin cholesterol acyltransferase correlated negatively with BMI (r = -0.40, P < .01), waist circumferences (r = -0.42, P < .001), and leptin levels (r = -0.40, P < .01). During multiple regression analyses, BMI was an independent predictor of LCAT after adjustments for age, sex, HOMA-IR, and HDL cholesterol. However, this was replaced by leptin and HOMA-IR when leptin was also included into the model. The CETP activities correlated with HOMA-IR (r = 0.33, P < .01), thiobarbituric acid reactive substances (r = 0.45, P < .001), and leptin (r = 0.36, P < .01) levels in univariate but not in multivariate models. Elevated leptin level is an independent predictor of low LCAT, but not PON1, activity. In a population with a wide range of BMI, LCAT correlates inversely with obesity and CETP directly with insulin resistance.

Background and Aim: Previous studies have demonstrated that oxidative stress is increased in obese patients. The high-density lipoprotein (HDL) associated human paraoxonase 1 (PON1) can inhibit low-density lipoprotein oxidation and has an antiatherogenic effect. Our objective was to assess the effects of orlistat therapy combined with diet on body mass index (BMI), waist circumference, lipid parameters, blood pressure, serum glucose level and PON1 activity., Methods and Results: A longitudinal, multicenter, randomized study with and without orlistat treatment was performed. One hundred thirty nine otherwise healthy, obese subjects were divided in to two groups: 78 persons received orlistat (120 mg three times a day) combined with diet while 61 persons were kept on diet only. Anthropometrical parameters, serum lipid levels and PON1 activity were measured at baseline and after 6 months of treatment. BMI and waist circumference were reduced more pronouncedly in the orlistat group than in the control group. Patients receiving orlistat also had significantly greater improvements in fasting blood glucose levels and blood pressure. The orlistat-treated group showed a greater reduction in total cholesterol and triglyceride levels. In addition, the serum PON1 activity in these patients was significantly increased compared to the diet-only group., Conclusions: The 6-month treatment with orlistat had a beneficial effect on the lipid profile and improved the antioxidant status by increasing serum PON1 activity. However, because of the limited therapeutic effectiveness, obese patients with hypercholesterolemia should receive additional lipid lowering medications.

257 patients from 33 centres were involved in a six-month study, the aim of which was to assess the effect of orlistat together with a diet. The authors examined how the treatment effected the anthropometrical and lipid parameters, extending the study to the aspect of paraoxonase activity in case of 25 patients. 44 patients dropped out during the study period due to the lack of sufficient diet compliance, whereas 3 patients had to stop the therapy because of the adverse event of flatus with discharge. On the average, the body mass of the patients decreased from 100.8 +/- 18.9 to 91.3 +/- 18.6 kg, i.e. by 9.5 kgs, while their BMI was reduced from 36.1 +/- 5.6 to 32.5 +/- 5.2 kg/m2 and the circumference of the waist changing from 119.1 +/- 20 to 108.3 +/- 15.1 cm, i.e. by 10.8 cms. The blood sugar level significantly decreased from 5.7 to 5.4, while the cholesterol concentration significantly dropped from 5.9 to 5.5, the triglyceride level being reduced from 2.4 to 2.1 mmol/l and blood pressure falling significantly from 136.6/86.9 to 129.9/81.6. All the above changes showed a significant decrease. However, the HDL-cholesterol level did not change. The serum paraoxonase activity significantly increased (143 +/- 49 vs 166 +/- 43 UL) along with the standardised values for HDL (PON/HDL), even compared to the control diet group. From the above results it may be concluded that orlistat tends to have an antioxidant effect.