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Objective: Adipose tissue inflammation plays an important role in the pathogenesis of obesity-associated complications, such as atherosclerosis. Adiponectin secreted from adipocytes has various beneficial effects including anti-inflammatory effect. Obesity often presents with hypoadiponectinemia. However, the mechanism and adiponectin movement in obesity remain uncharacterized. Here we investigated tissue distribution of adiponectin protein in lean and obese mice., Methods: Adiponectin protein levels were evaluated by enzyme-linked immunosorbent assay and western blotting. Adipose tissues were fractionated into mature adipocyte fraction (MAF) and stromal vascular fraction (SVF)., Results: Adiponectin protein was detected not only in MAF but also in SVF, which lacks adiponectin mRNA expression, of adipose tissue remarkably. SVF adiponectin protein level was higher in obese mice than in lean mice. The mechanism of adiponectin accumulation was investigated in adiponectin-deficient (APN-KO) mice after injection of plasma from wild-type mice. These mice showed accumulation of exogenous adiponectin, which derived from wild type mice, in adipose tissues, and the adiponectin was more observed in SVF of diet induced obese APN-KO mice than lean APN-KO mice. Among the adiponectin binding proteins, T-cadherin mRNA and protein levels in SVF of obese mice were remarkably higher than in lean mice. Oxidative stress levels were also significantly higher in SVF of obese mice than lean mice. Mechanistically, H2O2 up-regulated T-cadherin mRNA level in murine macrophages., Conclusions: The results demonstrated adiponectin targets to adipose SVF of obese mice. These findings should shed a new light on the pathology of adipose tissue inflammation and hypoadiponectinemia of obesity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: Inflammation is closely associated with the development of atherosclerosis and metabolic syndrome. Adiponectin, an adipose-derived secretory protein, possesses an anti-atherosclerotic property. The present study was undertaken to elucidate the presence and significance of adiponectin in vasculature., Methods and Results: Immunofluorescence staining was performed in aorta of wild-type (WT) mice and demonstrated that adiponectin was co-stained with CD31. Thoracic aorta was cut through and then aortic intima was carefully shaved from aorta. Western blotting showed the existence of adiponectin protein in aortic intima, while there was no adiponectin mRNA expression. Adiponectin knockout (Adipo-KO) and WT mice were administered with a low-dose and short-term lipopolysaccharide (LPS) (1 mg/kg of LPS for 4 hours). The endothelium vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were highly increased in Adipo-KO mice compared to WT mice after LPS administration., Conclusions: Adiponectin protein exists in aortic endothelium under steady state and may protect vasculature from the initiation of atherosclerosis.

Objective: Adiponectin, an adipocyte-derived protein, has potential antiatherogenic properties. Low levels of serum total-adiponectin (Total-APN) correlate with diabetes and coronary artery disease (CAD). Adiponectin and C1q form a protein complex in blood, and serum C1q-binding adiponectin (C1q-APN) can be measured. We investigated the correlation between C1q-APN and CAD in patients with type 2 diabetes mellitus (T2DM)., Methods: The study subjects were 107 outpatients with T2DM who underwent evaluation for CAD. Blood C1q, Total-APN, high-molecular weight-adiponectin (HMW-APN) and C1q-APN were measured by enzyme-linked immunosorbent assays., Results: Serum levels of C1q-APN/Total-APN ratio were higher in patients diagnosed with CAD (10.47±0.59, mean±SEM, n=54) than those without CAD (8.88±0.60, n=53, p=0.0482). Age- and sex-adjusted logistic regression analysis identified serum C1q-APN/Total-APN ratio and hypertension as significant and independent determinants of CAD. A high serum C1q-APN/Total-APN ratio was associated with 3.965-fold increase in CAD prevalence., Conclusions: High serum C1q-APN/Total-APN ratio correlates with CAD in T2DM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Atherosclerosis is a disease of blood vessels. Adiponectin is a biomarker of atherosclerosis. Adiponectin and C1q form a protein complex in human blood, and serum C1q-binding adiponectin (C1q-APN) can be measured. We investigated the relationship between various serum adiponectin parameters and polyvascular atherosclerosis score assessed by vascular ultrasonography, in subjects with type 2 diabetes mellitus (T2DM)., Methods: The study subjects were 108 outpatients with T2DM who underwent evaluation for atherosclerosis by vascular ultrasonography. Polyvascular atherosclerosis score represented the sum of atherosclerotic abnormalities in the aorta, carotid, renal and common iliac arteries. Blood C1q, total-adiponectin (Total-APN), high molecular weight-adiponectin (HMW-APN) and C1q-APN were measured by enzyme-linked immunosorbent assays. The estimated visceral fat area (eVFA) was measured by bioelectrical impedance., Results: Polyvascular atherosclerosis score correlated only with the C1q-APN/Total-APN ratio (p=0.018 for trend). There were no significant relationships between various adiponectin parameters and carotid maximum intima-media thickness and ankle-brachial index. Age-, sex-, eVFA-adjusted multiple logistic regression analysis that included the above variables identified serum C1q-APN/Total-APN ratio as the only significant and independent determinant of polyvascular atherosclerosis score., Conclusions: Serum C1q-APN/Total-APN ratio correlates with atherosclerosis detected by polyvascular vascular ultrasonography, independent of gender and visceral adiposity, in T2DM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Patients on maintenance hemodialysis (HD) have much higher levels of adiponectin (Total-APN). Adiponectin and C1q form a protein complex in human blood, and serum C1q-binding adiponectin (C1q-APN) can be measured. We recently reported that C1q-APN/Total-APN ratio rather than Total-APN correlated with atherosclerosis in diabetics. However, the characteristics of C1q-APN in HD patients remain unclear. The preset study investigated the characteristics of the adiponectin parameters including C1q-APN and also to clarify the relationship between various serum adiponectin parameters and atherosclerotic cardiovascular diseases (ACVD) in HD patients., Methods: The single cross-sectional study subjects were 117 Japanese patients (males/females = 61/56) on regular HD. Blood Total-APN, high molecular weight-adiponectin (HMW-APN), C1q-APN and C1q concentrations were measured by enzyme-linked immunosorbent assays. ACVD were defined as stroke, coronary and peripheral artery diseases, thoracic and abdominal aneurysms., Results: Stepwise regression analysis identified high-density lipoprotein-cholesterol (HDL-C) as the only significant and independent determinant of C1q-APN in males, and duration of HD as the only significant and independent determinant of C1q-APN in females. Stepwise regression analysis identified uric acid, low-density lipoprotein-cholesterol and triglyceride as significant and independent determinants of C1q-APN/Total-APN ratio in males, and leukocyte count and HDL-C as significant and independent determinants of C1q-APN/Total-APN ratio in females. Multiple logistic regression analysis identified inorganic phosphorus and C1q-APN or C1q-APN/C1q ratio as significant determinants of ACVD., Conclusions: Low serum C1q-APN and C1q-APN/C1q ratio, but not C1q-APN/Total-APN ratio, correlated with ACVD in HD patients., Trial Registration: ClinicalTrials.gov: UMIN http://000004318.

Objective: Adiponectin and C1q have similar sequences, exist abundantly in blood, and are produced by adipose tissues. The aim of this study was to examine whether adiponectin and C1q form protein-complex in blood and to know the clinical significance of the C1q-adiponectin (C1q-APN) complex in serum., Methods: The direct interaction between adiponectin and C1q was investigated by far western blotting and co-immunoprecipitation. The relationship between serum C1q-APN and various clinical features was analyzed in 329 Japanese men who underwent health check-up, including measurements of visceral (VFA) and subcutaneous fat area (SFA) by computed tomography (Victor-J study)., Results: Adiponectin bound to C1q in vitro and C1q-APN complex existed in human blood. C1q-APN complexes were identified in high- and middle-molecular weight forms of adiponectin in human serum by gel-filtration chromatography. Stepwise multiple regression analysis identified body mass index, VFA and SFA as significant determinants of serum C1q-APN level. Serum C1q-APN/Total-APN ratio correlated positively with cardiovascular risk factor accumulation in subjects with VFA ≥100 cm(2)., Conclusions: These results indicate that high- and middle-molecular forms of adiponectin partly consist of adiponectin-complex with other proteins including C1q and that the blood C1q-APN/Total-APN ratio may serve as a biomarker of the metabolic syndrome in general male subjects., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We measured circulating C1q-binding adiponectin (C1q-APN) levels before and after 3-month treatment with pioglitazone in people with type 2 diabetes. The results indicate 3-month treatment with pioglitazone reduces circulating levels of C1q-APN/total-adiponectin ratio without changes in body mass index., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

We investigated the relationship between intracoronary stenosis detected by multislice computed tomography and various clinical parameters in type 2 diabetic patients with hypertension treated with candesartan (n=42). The results showed that carotid intima-media thickness, but not visceral fat area or adiponectin, correlated significantly with intracoronary stenosis (p<0.05)., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Abstract Background The prevalence of gastroesophageal reflux disease (GERD) has been increasing worldwide. Abdominal obesity or visceral fat accumulation rather than simple obesity is associated with GERD. Previous reports demonstrated the association between GERD and type 2 diabetes mellitus (T2DM). Signification of visceral fat accumulation and adiponectin in T2DM patients with GERD remains unclear. The present study investigated the relationships between GERD symptoms, visceral fat accumulation and adiponectin in subjects with T2DM. Findings The study (ADMIT study) subjects were 66 Japanese T2DM outpatients, who answered the questionnaire regarding GERD symptoms in Frequency Scale for the Symptoms of GERD (FSSG), and were measured visceral fat area by bioelectrical impedance analysis. Patients with FSSG scores of more than 8 were considered as positive. The prevalence of FSSG score ≥ 8 and average FSSG score in T2DM subjects with the metabolic syndrome (Mets) were significantly higher compared to those without Mets. The prevalence of FSSG score ≥ 8 and average FSSG score in T2DM subjects with low levels of serum adiponectin were significantly higher compared to those with high levels of serum adiponectin. Moreover, the combination of Mets and hypoadiponectinemia had a multiplicative effect on GERD symptom score (p = 0.047). Conclusions Our study showed that the coexistence of MetS and low levels of serum adiponectin was associated with the higher prevalence of FSSG score ≥ 8 and the higher scores of GERD symptom in subjects with T2DM. Trial Registration UMIN 000002271.

Adiponectin is exclusively synthesized by adipocytes and exhibits anti-diabetic, anti-atherosclerotic and anti-inflammatory properties. Hypoadiponectinemia is associated in obese individuals with insulin resistance and atherosclerosis. However, the mechanisms responsible for hypoadiponectinemia remain unclear. Here, we investigated adiponectin movement using hetero parabiosis model of wild type (WT) and adiponectin-deficient (KO) mice. WT mice were parabiosed with WT mice (WT–WT) or KO mice (WT–KO) and adiponectin levels were measured serially up to 63 days after surgery. In the WT–KO parabiosis model, circulating adiponectin levels of the WT partners decreased rapidly, on the other hand, those of KO partners increased, and then these reached comparable levels each other at day 7. Circulating adiponectin levels decreased further to the detection limit of assay, and remained low up to day 63. However, adiponectin protein was detected in the adipose tissues of not only the WT partner but also WT–KO mice. In the diet-induced obesity model, high adiponectin protein levels were detected in adipose stromal vascular fraction of diet-induced obese KO partner, without changes in its binding proteins. The use of parabiosis experiments shed light on movement of native adiponectin among different tissues such as the state of hypoadiponectinemia in obesity. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis is an age-related disease. Adiponectin and C1q form a protein complex in human blood, and that serum C1q and C1q-binding adiponectin (C1q-APN) concentrations can be measured. We investigated circulating C1q and C1q-APN levels in Japanese men including elderly men. Findings: The study subjects were 509 Japanese men including elderly men. Serum levels of total adiponectin (Total-APN), high-molecular weight-adiponectin (HMW-APN), C1q-APN and C1q were measured by enzyme-linked immunosorbent assay. Total-APN, HMW-APN and C1q-APN, but not C1q, correlated significantly and positively with aging (r=0.26, r=0.24, r=0.17, p<0.01, respectively). The HMW-APN/Total-APN ratio correlated significantly and positively with aging (r=0.14, p<0.01). The C1q-APN/Total-APN ratio and C1q-APN/HMW-APN ratio correlated significantly and negatively with aging (r=-0.17, p<0.01, r=-0.12, p=0.01). C1q-APN/C1q correlated significantly and positively with aging (r=0.09, p=0.03). Multiple regression analysis identified age and body mass index as significant determinants of C1q-APN. Conclusions: The present study demonstrates that serum HMW-APN, C1q-APN, and Total-APN, but not C1q, correlated positively with aging. These preliminary results could form the basis for future research. Trial registration: Clinical Trial Registration Number: UMIN000004318 [ABSTRACT FROM AUTHOR]

Abstract: Aims: S100A8/A9 complex is an inflammation-associated biomarker, which binds toll-like receptor 4 and was associated with the receptor for advanced glycation end-products. S100A8 and S100A9 were accumulated in atherosclerotic lesions. High serum levels of S100A8/A9 are associated with acute coronary syndrome and atherosclerosis in type 2 diabetes mellitus (T2DM). However, association between serum S100A8/A9 levels and vulnerable plaque remains unclear. The present study investigated the relation between serum S100A8/A9 levels and relative plaque density (RPD) of the carotid artery determined by ultrasonography in T2DM. Methods: The study subjects were 72 consecutive T2DM outpatients (males/females=42/30), who underwent the carotid artery ultrasonography. RPD in the carotid artery was calculated by the formula; RPD=[density of the carotid plaque/density of vessel lumen]. Serum levels of adiponectin and S100A8/A9 were measured. Results: The median RPD was 2.1. Patients with low RPD (≤2.1) were significantly more likely to have metabolic syndrome, nephropathy, coronary artery disease, and peripheral artery disease, and higher levels of S100A8/A9, S100A8/A9-to-adiponectin ratio, and uric acid, compared to those with high RPD (>2.1). Conclusions: T2DM patients with low RPD had higher prevalence of metabolic syndrome, cardiovascular diseases and higher serum S100A8/A9 levels, compared to those with high RPD. [Copyright &y& Elsevier]

Abstract: Aims: Mineralocorticoid receptor (MR) blockade ameliorated insulin resistance with improvements in adipocytokine dysregulation, inflammation, and excess of reactive oxygen species (ROS) in obese adipose tissue and adipocytes, but its mechanism has not been clarified. The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), producing active glucocorticoids, is highly expressed in adipocytes and glucocorticoids bind to MR with higher affinity than to glucocorticoid receptor (GR). We investigated whether glucocorticoids effect on adipocytokines and ROS through MR in adipocytes. In addition, fat distributions of MR and GR were investigated in human subjects. Methods and Results: Corticoid receptors and their target genes were examined in adipose tissue of obese db/db mice. 3T3-L1 adipocytes were treated with glucocorticoids, H2O2, MR antagonist eplerenone (EP), GR antagonist RU486 (RU), MR-siRNA, and/or N-acetylcysteine. Human adipose tissues were obtained from seven patients who underwent abdominal surgery. The mRNA levels of MR and its target gene were higher in db/db mice than in control db/m +mice. In 3T3-L1 adipocytes, glucocorticoids, similar to H2O2, caused the dysregulation of mRNA levels of various genes related to adipocytokines and the increase of intracellular ROS. Such changes were rectified by MR blockade, not by GR antagonist. In human fat, MR mRNA level was increased in parallel with the increase of body mass index (BMI) and its increase was more significant in visceral fat, while there were no apparent correlations of GR mRNA level to BMI or fat distribution. Conclusion: Glucocorticoid-MR pathway may contribute to the obesity-related adipocytokine dysregulation and adipose ROS. [Copyright &y& Elsevier]