Adipocytokine Concentrations Research Articles

Is plasma 25(OH) D related to adipokines, inflammatory cytokines and insulin resistance in both a healthy and morbidly obese population?

To analyse in a cohort of healthy subjects and in a group of morbidly obese patients, we studied the association amongst 25(OH) D and plasma concentrations of adipocytokines, inflammatory cytokines and insulin resistance. We also aimed to determine whether vitamin D-deficient patients showed a greater inflammatory profile. In the observational study that the authors conducted, plasma concentrations of 25(OH) D, leptin, resistin, adiponectin and interleukine-18 were determined in 134 healthy men and 127 women. In the population consisting of 44 patients with morbid obesity, plasma concentrations of 25(OH) D, leptin, resistin, adiponectin, interleukine-18, soluble tumor necrosis factor receptors 1 and 2 and C-reactive protein were analysed. In the healthy population, plasma 25(OH) D showed a negative correlation with body mass index, body fat, waist, hip circumference and with leptin. However, no significant associations were found amongst 25(OH) D and plasma concentrations of resistin, adiponectin or interleukine-18. Patients with vitamin D deficiency showed higher body mass index, fat mass percentage and higher leptin concentrations compared with subjects with normal 25(OH) D concentrations. In the morbidly obese subjects, 25(OH) D did not correlate with leptin, resistin, adiponectin, interleukine-18, soluble tumor necrosis factor receptors 1 and 2 or with C-reactive protein. In patients with morbid obesity, no differences were found in adipokines and inflammatory cytokines concentrations regarding 25(OH) D status. No associations were found either between 25(OH) D and plasma glucose and insulin resistance or with lipid profile. Plasma 25(OH) D concentrations are associated with adiposity markers but not with adipocytokines implicated in inflammation. This lack of association does not support a major role of 25(OH) D in the pro-inflammatory environment observed in morbidly obese subjects. In addition, subjects with vitamin D deficiency are not characterized by a greater inflammatory state.

Adipocytokines, insulin resistance, and coronary atherosclerosis in rheumatoid arthritis

The prevalence of subclinical coronary atherosclerosis is increased in patients with rheumatoid arthritis (RA), and the increased risk is associated with insulin resistance. Adipocytokines have been linked to obesity, insulin resistance, inflammation, and coronary heart disease in the general population. This study was undertaken to examine the hypothesis that adipocytokines affect insulin resistance and coronary atherosclerosis among patients with RA. The coronary calcium score, homeostatic model assessment for insulin resistance (HOMA-IR) index, and serum adipocytokine (leptin, adiponectin, resistin, and visfatin) concentrations were determined in 169 patients with RA. The independent effect of each adipocytokine on insulin resistance according to the HOMA-IR index and on coronary artery calcification determined by electron beam computed tomography was assessed in models adjusted for age, race, sex, body mass index (BMI), traditional cardiovascular risk factors, and inflammation mediators. In addition, an interaction analysis was performed to evaluate whether the effect of the HOMA-IR index on the coronary calcium score is moderated by adipocytokines. Increased concentrations of leptin were associated with a higher HOMA-IR index, even after adjustment for age, race, sex, BMI, traditional cardiovascular risk factors, and inflammation mediators (P < 0.001), but concentrations of visfatin (P = 0.06), adiponectin (P = 0.55), and resistin (P = 0.98) showed no association with the HOMA-IR index. None of the adipocytokines was independently associated with the coronary calcium score (all P > 0.05). Serum leptin concentrations showed a significant interaction with the HOMA-IR index (P for multivariate interaction = 0.02). Increasing leptin concentrations attenuated the increased risk of coronary calcification related to insulin resistance. Serum concentrations of the other adipocytokines showed no significant interactions with the HOMA-IR index (each P > 0.05). Leptin is associated with insulin resistance in patients with RA but, paradoxically, attenuates the effects of insulin resistance on coronary calcification.

Increased Frequency of Metabolic Syndrome and Its Individual Metabolic Abnormalities in Japanese Patients With Primary Gout

Gout patients are frequently complicated with hypertension, obesity, dyslipidemia, and/or impaired glucose tolerance, which are components of the metabolic syndrome and risks for atherosclerotic diseases. To determine the relationship between metabolic syndrome and gout, as well as plasma concentrations of adipocytokines in gout patients. The frequency of metabolic syndrome as well as its constituents were investigated in 258 male gout patients and 111 males who attended an annual check-up examination. In addition, plasma concentrations of adipocytokines were measured in 107 of the patients. Gout patients had a higher prevalence of metabolic syndrome as compared with the controls (36.4% vs. 15.3%, P < 0.0001). In addition, frequencies of individual metabolic abnormalities, such as waist circumference >85 cm, hypertension, and hypertriglyceridemia, were significantly increased in the gout patients as compared with the controls. Furthermore, uric acid over-production gout had a significantly higher prevalence of metabolic syndrome as compared with uric acid under-excretion gout (48.6% vs. 32.4%, P < 0.001). The plasma concentrations of leptin and plasminogen activator inhibitor-1 were significantly higher in the patients (P < 0.05, respectively), while that of adiponectin and the adiponectin/leptin ratio were significantly decreased in the gout patients as compared with the controls (P < 0.05, respectively). A higher prevalence of metabolic syndrome in gout patients may in part contribute to susceptibility to atherosclerotic diseases. Therefore, more attention should be paid to the presence of metabolic syndrome in gout patients to reduce their risk for cardiovascular disease complications.

Relationships between serum adiponectin, leptin concentrations and bone mineral density, and bone biochemical markers in Chinese women

Adiponectin and leptin, as the main circulating peptides secreted by adipose tissue, are potential contributors to bone metabolism. However, their association with bone mineral density (BMD) is unknown. We investigated whether these serum adipocytokines concentrations are associated with BMD and bone turnover markers. Serum adiponectin, leptin concentrations, bone turnover biochemical markers, and BMD were determined in 265 premenopausal and 336 postmenopausal Chinese women. In postmenopausal Chinese women, the multiple linear stepwise regression analysis showed that year since menopause, lean mass, estradiol, and adiponectin, but not fat mass, leptin, were independent predictors of BMD in postmenopausal Chinese women. However, in premenopausal Chinese women, adiponectin was not the predictor of BMD. The significant positive correlations between adiponectin and bone-specific alkaline phosphatase (BAP), bone cross-linked N-telopeptides of type I collagen (NTX) were found only in postmenopausal women. Serum BAP, and NTX, but not adiponectin, decreased in response to alendronate therapy. Adiponectin was an independent predictor of BMD, and positively correlated with bone turnover biochemical markers in postmenopausal Chinese women, but not premenopausal women. It suggested that adiponectin may exert a negative effect on bone mass by promoting excessive bone resorption associated with bone loss. However, these effects may be mediated by menopausal status.

Adipocytokines and endothelial function in preeclamptic women

Visceral fat accumulation stimulates the production of adipocytokines in patients with metabolic syndrome. Excess body weight gain during pregnancy is a risk factor for preeclampsia. To evaluate whether the pathogenesis of preeclampsia is similar to that of metabolic syndrome, we measured plasma adipocytokine concentrations and investigated the association between plasma adiponectin concentrations and body weight gain or endothelial function in preeclamptic women. We investigated 15 preeclamptic and 17 women with uncomplicated pregnancies. Women with preeclampsia had significantly lower plasma concentrations of adiponectin (10.2+/-2.0 vs. 7.3+/-2.2 microg ml(-1), P<0.01), but higher concentrations of leptin, plasminogen activator inhibitor-1, interleukin-6, vascular cell adhesion molecule-1, E-selectin and C-reactive protein. Plasma triglyceride levels were significantly higher in preeclamptic patients, but the levels of other lipids did not differ significantly between the two groups. We found that flow-mediated vasodilation was significantly decreased in preeclamptic women compared with controls (10.6+/-6.4 vs. 3.8+/-2.0%, P<0.001). Plasma adiponectin concentrations correlated negatively with body mass index (r=-0.50, P<0.05) and body weight gain during pregnancy (r=-0.63, P<0.01), and positively with flow-mediated vasodilation (r=0.50, P<0.05) in preeclamptic women, but not in women with uncomplicated pregnancies. Similar to the patients with metabolic syndrome, we found that dysregulation of adipocytokines, such as low adiponectin levels and high levels of other adipocytokines, and excess body weight gain during pregnancy, may decrease plasma adiponectin concentrations that are associated with endothelial dysfunction in preeclamptic women.

Adiponectin and Prostate Cancer Mortality: To Be or Not to Be Skinny?

Obesity is one of the biggest public health crises of our day. In the United States, 1 in 3 adult men is obese. This rate is staggeringly high compared with obesity rates in other countries—notably those in Asia, where obesity rates are <5%. Obesity is well known to increase the risk for numerous medical problems, such as diabetes, heart disease, and hypertension, and has been linked with the incidence of and the mortality from multiple cancers. In terms of prostate cancer, the relationship with obesity is complex (1). In the 20 000-foot view, obesity appears to be associated with a slightly decreased risk in the incidence of prostate cancer, but it is also associated with a clear and consistent, albeit modest, increased risk of prostate cancer mortality. Multiple molecular mechanisms have been proposed to explain these observations (2). Ultimately, the contributions from each of these mechanisms remain unclear. Therefore, it is important to continue to investigate the pathways that link obesity with aggressive prostate cancer. With that goal in mind, Li and coworkers (3) describe in this issue of Clinical Chemistry their investigation of whether prediagnostic concentrations of adipocytokines (leptin or adiponectin) correlated with prostate cancer incidence or disease aggressiveness/mortality. This study used frozen serum samples from nearly 1300 adult male participants nested within the Physicians’ Health Study. The strength of this analysis was the fact that samples were collected before the diagnosis of prostate cancer. The design of this prospective cohort study thus avoids the limitations of case–control studies, in which biomarkers are measured in men already known to have the disease. The problem with the case–control approach is that increased biomarker concentrations may be due to a tumor already present rather than to an increase in a biomarker that causes the …

The effect of rosiglitazone on insulin sensitivity and mid‐thigh low‐density muscle in patients with Type 2 diabetes

We examined the effect of rosiglitazone on insulin sensitivity, abdominal fat and mid-thigh intramuscular fat distribution, and plasma concentrations of adipocytokines in patients with Type 2 diabetes. Rosiglitazone was administered at a daily dose of 4 mg to 42 Type 2 diabetes patients [age 32-70 years, body mass index (BMI) 17.5-32.6 kg/m(2), 15 women, 27 men] for 12 weeks. Various anthropometric and metabolic profiles, plasma adiponectin, leptin, and resistin levels were measured, and insulin resistance was calculated from the short insulin tolerance test. Body fat composition was assessed by computed tomography. Twelve weeks' rosiglitazone treatment resulted in improved insulin resistance despite increases in body weight and BMI. There was a significant decrease in abdominal visceral adipose tissue area (145 +/- 65.6 vs. 129 +/- 73.1 cm(2), P = 0.049). Mid-thigh low-density muscle area (TLDMA) increased from 23 +/- 9.6 to 26 +/- 8.2 cm(2) (P = 0.009). There were significant changes in plasma adipocytokines, but they were not significantly correlated with changes in insulin resistance. Rosiglitazone treatment resulted in an improvement of insulin responsiveness in Type 2 diabetic subjects, which was associated with the redistribution of visceral and subcutaneous adipose tissue, an increase in TLDMA, and changes in serum adipocytokine levels. Further studies are needed to elucidate the insulin sensitizing mechanism of rosiglitazone on peripheral skeletal muscles.

Oxidative Stress Associated with Rapid Weight Reduction Decreases Circulating Adiponectin Concentrations

The effect of stress associated with acute weight reduction on adipocytokine production is incompletely understood. In the present study, we have investigated the changes in circulating adipocytokine concentrations and urinary concentrations of stress markers in male collegiate wrestlers during acute weight reduction for a competition. Twenty healthy Japanese male wrestlers (18-22 years of age) who participated in the national collegiate wrestling tournament were studied. Body weight, body fat amount, serum testosterone, serum leptin, serum adiponectin, urinary 8-hydroxy-2'- deoxyguanosine (8-OHdG) and urinary biopyrrins were analyzed during acute weight reduction for the competition. Body weight, body fat amount and the serum concentrations of testosterone, leptin and adiponectin significantly decreased on the day of weigh-in compared with the levels 12 days before weigh-in. In contrast, urinary concentrations of 8-OHdG and biopyrrins significantly increased on the day of weigh-in compared with the concentrations 12 days before weigh-in. A positive correlation was observed between the serum concentrations of adiponectin and testosterone, and a negative correlation was observed between the concentrations of serum adiponectin and urinary biopyrrins. The present results suggest that rapid weight reduction increases the urinary concentrations of stress markers, which is associated with a decrease in serum concentrations of adiponectin.

Effect of postprandial lipemia on plasma concentrations of A-FABP, RBP-4 and visfatin

Background and aims Several studies indicate that changes in the plasma concentrations of adipocyte-fatty acid binding protein (A-FABP), retinol binding protein-4 (RBP-4) and visfatin are associated with chronic states of insulin resistance. Recent studies have shown that postprandial lipemia induces an acute state of insulin resistance. The aim of this study was to investigate the effect of postprandial lipemia on the plasma concentrations of A-FABP, RBP-4 and visfatin. Methods and results In a within-subject crossover study, we administered a standardized high-fat meal to 24 healthy subjects (12 males and 12 females). Plasma concentrations of adipocytokines were measured in the morning after an overnight fast and during postprandial lipemia, i.e. 2, 4 and 6 hours after meal ingestion (postprandial experiment). To exclude potential confounding factors affecting the adipocytokine plasma concentrations, a control experiment without meal ingestion was performed over the same time period (postabsorptive control experiment). Comparing plasma concentrations of A-FABP, RBP-4 and visfatin between the postprandial and the postabsorptive control experiments, we found no significant differences. Within either of the two experiments, a decrease of A-FABP was noted reaching, however, statistical significance only in the postprandial experiment, i.e. 2 and 4 hours after meal ingestion. Conclusion Postprandial lipemia has no significant effect on the plasma concentrations of visfatin, A-FABP or RBP-4 in relation to their postabsorptive plasma profiles. We conclude that prolonged states of insulin resistance are required to affect plasma concentrations of these adipocytokines.

Adipocytokines in systemic lupus erythematosus: relationship to inflammation, insulin resistance and coronary atherosclerosis

We tested the hypothesis that concentrations of adipocytokines are altered in SLE and associated with coronary atherosclerosis, insulin resistance and inflammation. Concentrations of resistin, leptin, adiponectin and visfatin were measured in 109 patients with SLE and 78 control subjects. Coronary calcification was measured using electron beam-computed tomography, and insulin resistance was defined by the homeostasis model assessment index. Concentrations of adiponectin (28.7 +/- 17.9 vs 22.0 +/- 15.3 microg/mL, P = 0.003), leptin (41.1 +/- 49.9 vs 19.8 +/- 24.6 ng/mL, P < 0.001) and visfatin (7.5 +/- 10.5 vs 4.5 +/- 2.8 ng/mL, P < 0.001) were higher in patients with SLE than in controls. These differences remained significant after adjustment for age, race, sex and body mass index (BMI; all P values < 0.02). Concentrations of resistin (10.7 +/- 7.6 vs 9.1 +/- 5.1 ng/mL, P = 0.41) did not differ in patients and controls. In patients with SLE, leptin was positively associated with BMI (rho = 0.80, P < 0.001), insulin resistance (rho = 0.46, P < 0.001) and C-reactive protein (CRP) (rho = 0.30, P = 0.002), whereas adiponectin was negatively associated with the same factors (rho = -0.40, P < 0.001; rho = -0.38, P < 0.001; rho = -0.22, P = 0.02, respectively). None of the adipocytokines were associated with coronary atherosclerosis in SLE. In conclusion, patients with SLE have increased concentrations of adiponectin, leptin and visfatin. Lower concentrations of adiponectin and higher concentrations of leptin are associated with insulin resistance, BMI and CRP in patients with SLE.

Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis

Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA. We compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNFalpha]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNFalpha, IL-6, and CRP). Concentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32-4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI (rho = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17-0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42-1.73], P = 0.67). Concentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced, levels of radiographic joint damage.

Circulating and Uteroplacental Adipocytokine Concentrations in Preeclampsia

The adipokines adiponectin and leptin may contribute to preeclampsia; however, the reports are conflicting. We explored the issue further. We studied 25 pregnant women with normal pregnancy in first, 25 in second, and 30 in third trimesters, 15 healthy nonpregnant women, and 32 women with preeclampsia. We used enzyme-linked immunosorbent assay to measure human plasma adiponectin (ng/mL) and leptin (ng/mL) concentrations. We also investigated adiponectin and leptin expression by quantitative messenger RNA in fat, decidua, and placenta tissues in a second study. Prepregnancy body mass index was not different in preeclamptic and nonpreeclamptic women. Plasma adiponectin concentrations increased throughout normal pregnancy, compared to nonpregnant women. The values increased in every trimester but were invariably lower in women with preeclampsia. Adiponectin nonetheless correlated inversely with prepregnancy body mass index. Such correlations were not found in women with preeclampsia. Plasma leptin in contrast decreased during pregnancy in every trimester. Leptin values were much higher in preeclamptic than in nonpreeclamptic women. Leptin expression was increased in the uteroplacental unit and in fat tissue of preeclamptic, compared to nonpreeclamptic women, while no differences in adiponectin expression were found. Adiponectin increases in normal pregnancy but remains correlated with prepregnancy body mass index. Plasma leptin decreases in normal pregnancy. In preeclamptic women, the normal adipokine responses are perturbed and this could be of pathophysiological significance.

Two-month effects of individualized exercise training with or without caloric restriction on plasma adipocytokine levels in obese female adolescents

Objectives To examine if, in young obese patients, an individualized training programme in association with a caloric restriction programme which had an effect on whole-body lipid oxidation, was able to induce changes on plasma adipocytokine concentrations. Materials and methods Twenty-seven obese female adolescents participated in the study. Whole-body lipid oxidation during exercise was assessed by indirect calorimetry during a graded cycle ergometer test. Body mass (BM), body mass index (BMI), percentage of body fat (%BF), insulin homeostasis model assessment (HOMA-IR) and fasting levels of circulating adipocytokines were assessed prior and after a two-month diet programme, individualized training programme targeted at Lipox max corresponded to the power at which the highest rate of lipids was oxidized and combined diet/training programme. Results The diet/training programme induced both a shift to a higher-power intensity of Lipox max (+27.8 ± 5.1 W; p < 0.01) and an increase of lipid oxidation at Lipox max (+96.8 ± 16.2 mg/min; p < 0.01). The enhancement in lipid oxidation was significantly ( p < 0.01) correlated with the diet/training-induced improvement in %BF ( r = −0.47), HOMA-IR ( r = −0.66), leptin ( r = −0.41), TNF-α ( r = −0.48), IL-6 ( r = −0.38), adiponectin ( r = 0.43) and resistin ( r = 0.51). Conclusion This study showed that in obese female adolescents a moderate training protocol targeted at Lipox max and combined with a diet programme improved their ability to oxidize lipids during exercise, and that this improvement was associated with changes in plasma adipocytokine concentrations.

Circulating Leptin and Adiponectin Concentrations During Tumor Necrosis Factor Blockade in Patients with Active Rheumatoid Arthritis

Adipocytokines, including leptin and adiponectin, may play an important role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of longterm therapeutic tumor necrosis factor (TNF) blockade on adipocytokine concentrations in patients with RA. We studied 58 RA patients starting anti-TNF therapy and 58 healthy controls matched for age, sex, and body mass index (BMI). Fasting blood samples were drawn at baseline, 2 weeks, and 6 months after the start of anti-TNF therapy and serum levels of leptin and adiponectin were measured. Patients with RA had increased adiponectin (p<0.001) and similar leptin concentrations compared with the controls. Leptin concentrations were significantly higher in patients with high BMI (p<0.001) and correlated positively with BMI at all timepoints (r>0.75). In contrast, serum adiponectin tended to be higher in lean RA patients and did not correlate with BMI at any timepoint. There were no clear correlations between serum concentrations of adipocytokines and disease activity (Disease Activity Score 28). Short or longterm TNF blockade alone had no influence on circulating leptin and adiponectin concentrations. Patients treated with anti-TNF and concomitant corticosteroids on a stable basis showed a significant decrease in adiponectin levels after 6 months of therapy (p<0.025). In patients with RA, chronic inflammation and its suppression during anti-TNF therapy have limited influence on plasma leptin concentrations, while significantly decreasing circulating adiponectin levels. Our findings question the suggested key role of inflammatory markers in regulating adipocytokine patterns in RA.

Relation of visfatin to cardiovascular risk factors and adipocytokines in patients with impaired fasting glucose

ObjectiveThe discovery of visfatin has great potential to significantly enhance our understanding of impaired fasting glucose and diabetes mellitus. The aim of the present study was to explore the relation of visfatin concentrations to cardiovascular risk factors and serum adipocytokine concentrations in patients with impaired fasting glucose. MethodsA sample of 55 patients with impaired fasting glucose was analyzed in a prospective way. All patients with a 2-wk weight-stabilization period before recruitment were enrolled. Weight, blood pressure, basal glucose, lipoprotein(a), C-reactive protein, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triacylglycerols, blood, and adipocytokines (visfatin, leptin, adiponectin, resistin, tumor necrosis factor-α [TNF-α], and interleukin-6) levels were measured. Tetrapolar impedancometry, indirect calorimetry, and prospective serial assessment of nutritional intake with 3-d written food records were performed. ResultsFourteen men (25.5%) and 41 women (74.5%), with a mean age of 57.3 ± 11.7 y and mean body mass index of 35.8 ± 3.6 kg/m2, were included. Patients were divided in two groups by median visfatin value (18.2 ng/mL): group I had low values and group II had high values. Patients in group I had greater weight, body mass index, fat mass, fat-free mass, and adiponectin than patients in group II. Patients in group II had higher total cholesterol, low-density lipoprotein cholesterol, resistin, and TNF-α levels than patients in group I. In the multivariate analysis with age- and sex-adjusted basal visfatin concentration as a dependent variable, only TNF-α remained an independent predictor in the model (F = 8.4, P < 0.05), with an inverse correlation. Visfatin concentration decreased 7.33 ng/mL (95% confidence interval 2.10–12.58) for each nanogram per milligram of TNF-α increase. ConclusionOnly TNF-α is related in an independent way to serum visfatin levels.

Cocoa consumption for 2 wk enhances insulin-mediated vasodilatation without improving blood pressure or insulin resistance in essential hypertension

Background:Essential hypertension is characterized by reciprocal relations between endothelial dysfunction and insulin resistance. Cocoa flavanols stimulate production of the vasodilator nitric oxide from vascular endothelium. Objective:The objective was to test the hypothesis that consumption of cocoa may simultaneously lower blood pressure, improve endothelial dysfunction, and ameliorate insulin resistance in subjects with essential hypertension. Design:We conducted a randomized, placebo-controlled, double-blind, crossover trial of a flavanol-rich cocoa drink (150 mL twice a day, ≈900 mg flavanols/d) in individuals with essential hypertension (n = 20). Antihypertensive medications were discontinued before study enrollment. After a 7-d cocoa-free run-in period, cocoa or flavanol-poor placebo (≈28 mg flavanols/d) treatment for 2 wk was followed by a 1-wk washout and then crossover to the other treatment arm. Blood pressure was measured thrice weekly. At baseline and after each treatment period, we assessed insulin sensitiv-ity (hyperinsulinemic-isoglycemic glucose clamp) and insulin-stimulated changes in brachial artery diameter and forearm skeletal muscle capillary recruitment (Doppler ultrasound with or without microbubble contrast). Results:Cocoa treatment for 2 wk increased insulin-stimulated changes in brachial artery diameter when compared with placebo [median percentage increase from baseline (25th–75th percentile): 8.3 (4.2–11.3) compared with 5.9 (−0.3 to 9.6);P < 0.04]. Nevertheless, cocoa treatment did not significantly reduce blood pressure or improve insulin resistance and had no significant effects on skeletal muscle capillary recruitment, circulating plasma concentrations of adipocytokines, or endothelial adhesion molecules. Conclusions:Daily consumption of flavanol-rich cocoa for 2 wk is not sufficient to reduce blood pressure or improve insulin resistance in human subjects with essential hypertension. This trial was registered atclinicaltrials.gov asNCT00099476.

Serial Plasma Concentrations of Adipocytokines during Chemotherapy in Children with Acute Lymphoblastic Leukemia

Disturbances in the production of adipocyte-derived hormones may represent a new link explaining the well-known relationship between obesity and increased prevalence of malignancies. Very few studies have evaluated adipokines concentration at diagnosis and during remission of a cancer. Purpose of our study was to investigate adipocytokines secretion, at diagnosis and during chemotherapy in children with acute lymphoblastic leukemia (ALL).Patients and Methods: Measurements were performed at diagnosis, after the induction-consolidation phase and at standard time points before each cycle in nine consecutive patients with ALL aged 2–7 years (median 4.3 yrs). All patients suffered from ≥5% BMI reduction in the 6 months before recruitment. BMI and leukemic burden were estimated at the same time points and correlated with adipocytokines levels. Nine healthy children matched for age and sex were used as controls.Results: At diagnosis, mean adiponectin levels were low (12.6±2.3 μg/ml vs. 18.2±2.4 μg/ml in controls, p<0.0001) and mean leptin and resistin levels were high (27.4±4.2 ng/ml vs. 17.8 ± 3.4 ng/ml in controls, p<0.001 and 5.2±1.2ng/ml vs. 3.2±1.1ng/ml in controls, p<0.001, respectively). Compared to baseline values, mean adiponectin levels increased significantly to 16.6±2.9 μg/ml before the end of maintenance phase (p=0.024), while leptin and resistin fluctuated and stabilized at significantly lower levels (17.1±3.9 ng/ml, p=0.018 and 3.4±0.9 ng/ml, p=0.020, respectively), after the 8th cycle of chemotherapy. Mean adiponectin was still low, compared with controls, (p<0.001), even after the 8th cycle. Delta (final-baseline) mean adiponectin was positively correlated with delta mean BMI-SD score of the patients (0.512, p=0.016), while delta mean leptin and resistin was negatively correlated with it (−0.626, p=0.009, and −0.527, p=0.013, respectively). However, when considering for lipids, LDH or leukemic burden, the positive association of adiponectin with BMI (0.087, p>0.05) and the negative association of leptin and resistin with BMI do not persist (−0.098, p>0.05 and −0.094, p>0.05 respectively). Delta mean adiponectin was negatively correlated with leukemic burden (−0.439, p=0.019), while delta mean leptin and resistin was positively correlated with it (0.581, p=0.011 and 0.375, p=0.031, respectively). Delta mean adiponectin was negatively correlated with delta mean LDH (−0.315, p=0.041), delta mean triglycerides (−0.412, p=0.025) and positively correlated with delta mean HDL-C (0.306, p=0.042), while delta mean leptin and resistin was positively correlated with delta mean LDH (0.423, p=0.028, and 0.387, p=0.032, respectively), delta mean triglycerides (0.372, p=0.035, and 0.523, p=0.022, respectively) and negatively correlated with delta mean HDL-C (−0.467, p=0.020, and −0.356, p=0.034, respectively). Finally, delta mean BMI-SD was positively correlated with delta mean HDL-C (0.502, p=0.018) and negatively with delta triglycerides (−0.420, p=0.023) and delta LDH (−0.605, p<0.010).Conclusion: Our results suggest that low serum adiponectin level and high leptin and resistin level are present in almost all patients with ALL at diagnosis. This is probably due to neuroendocrine imbalance and inflammation. The abnormalities are restored during remission. More studies are needed to substantiate associations between leukemia development and these hormones in the population of ALL children.

Adipocytokines and risk of stroke in older people: a nested case–control study

Inflammation may play an important role in atherothrombosis and in promoting cerebral damage after stroke. We hypothesized that plasma adipocytokine concentrations would be associated with risk of stroke in older people. Nested case-control study from the Prospective Study of Pravastatin in the Elderly (PROSPER). Subjects were aged 70-82 years and followed up for a mean of 3.2 years: 266 incident stroke cases (179 confirmed as ischaemic) were compared with 532 controls matched for age, gender and treatment allocation (pravastatin or placebo). Adipocytokines [adiponectin, interleukin- (IL-)18 and tumour necrosis factor (TNF)alpha] were measured on stored baseline plasma samples. Elevated plasma adiponectin was associated with lower risk of ischaemic stroke on univariate analysis: odds ratio (OR) 0.78 per 1 SD increase (95% CI 0.62-0.97). There were no associations of IL-18 or TNFalpha with risk for ischaemic or total strokes. In multivariate models the independent predictors of ischaemic stroke were prior cerebrovascular accident (OR 2.68, 95% CI 1.60-4.50), any alcohol use (1.98, 1.33-2.94), triglycerides (1.40, 1.11-1.77), Barthel score (0.75, 0.58-0.96) and known diabetes (1.72, 1.04-2.83); adiponectin, IL-18 and TNFalpha did not contribute. A similar pattern of risk was seen for total stroke. Reduced adiponectin may have a modest role in the aetiology of ischaemic stroke in older people, however IL-18 and TNFalpha are unlikely to play any important part. These adipocytokines do not have clinical predictive utility; history of prior cerebrovascular accident, known diabetes mellitus, prior disability and higher alcohol intake explain much of the stroke risk.

A highly sensitive enzyme-linked immunosorbent assay for quantification of adipocytokines secreted by mouse adipocytes

Abstract The mouse preadipocyte 3T3-L1 line is the most useful cell line for the study of adipocytes. Adipocytes secrete adipocytokines, and abnormal adipocytokine production can cause the metabolic syndrome. Although it is important to understand the characteristics of mouse adipocytokine secretion, it is difficult to quantify these products because they are produced in low concentrations. Here, we developed a highly sensitive enzyme-linked immunosorbent assay (ELISA) for detecting the concentrations of mouse adipocytokines, such as TNFα and leptin. In this method, the antigen was sandwiched by using goat- and rabbit-derived polyclonal antibodies, and the fluorescence intensity produced in the reaction with 4-methylumbelliferyl-β-galacto-sidase pyranosidase (MUG) was measured. TNFα and leptin could be measured at concentrations as low as approximately 1 pg/ml. By using our ELISA method, we also measured the concentrations of TNFα and leptin in mouse 3T3-L1 preadipocytes and adipocytes. The differentiation of preadipocytes into adipocytes enhanced TNFα production and secretion and reduced the leptin production. The amount of TNFα produced in the adipocytes was 3.0 ng/mg-protein; this amount was considerably higher than that of leptin.

First trimester adipocytokine concentrations and risk of developing gestational diabetes later in pregnancy

Adipocytokines are important regulators of insulin resistance. The aim of this study was to compare maternal adipocytokines in early pregnancy among women diagnosed with and without gestational diabetes (GDM) months later. A nested case-control study. Adiponectin, resistin and interleukin-6 (IL-6) were measured in 59 nulliparous women (30 women with GDM and 29 controls) in plasma obtained in early pregnancy. Patients underwent routine testing for GDM in late pregnancy. Adiponectin was measured using radioimmunoassay. Resistin and IL-6 were measured by ELISA. Statistical analysis included Student's t-test, logistic regression and Pearson's correlation. Groups were not different by baseline descriptors or obstetric outcomes. Mean gestational age at sampling was 9.3 +/- 2.6 weeks. Adiponectin was lower (P < 0.001) in women who later developed GDM compared to controls (4.3 +/- 0.4 vs. 6.9 +/- 0.6 microg/ml). Adiponectin was negatively associated with the development of GDM (P = 0.002; OR: 0.70, 95% CI: 0.56, 0.88) and the association persisted in multivariable analysis controlling for confounders (P = 0.01; OR: 0.69, 95% CI: 0.52, 0.92). Women with first trimester adiponectin concentrations < 25th% were 10 times more likely to be diagnosed with GDM (OR 10.2; 95% CI 1.3, 78.7). Early adiponectin concentrations negatively correlated with BMI (P = 0.01; r = -0.32) and subsequent 50 g glucose challenge (P = 0.03; r =-0.29). Mean resistin and IL-6 concentrations were not different between the two groups. Women with GDM have evidence of altered adipocyte function as measured by adiponectin early in pregnancy, months before the clinical diagnosis of GDM is traditionally made.