Dynamic changes in plasma total and high molecular weight adiponectin levels in acute heart failure.

BACKGROUND: Elevated levels of total plasma adiponectin (APN) and high molecular weight (HMW)-APN have been observed in chronic heart failure (HF) and are associated with poor prognosis, however, the response of APN levels in acute HF is not known. The purpose of this study was to clarify the dynamic changes of the plasma total APN, HMW-APN levels, and the ratio of HMW-APN to total APN (HMWR) in acute HF. METHODS: From February 2006 to January 2007, 20 patients with acute HF (non-ischemic and non-valvular origin, 17 men, aged 63±11 years) were enrolled, and blood was sampled before the onset of the treatment and at discharge. Ten patients admitted for the treatment of supraventricular arrhythmia (8 men, aged 45±13 years) were included as controls. RESULTS: The medians and interquartile ranges of the plasma total APN, HMW-APN levels, and HMWR at admission were 20.8 (14.5-38.9) µg/mL, 12.4 (7.7-23.3) µg/mL, and 0.60 (0.50-0.69), respectively. The total APN and HMW-APN values were significantly higher than the values of the control. The plasma total APN, HMW-APN, and HMWR values at discharge decreased to 19.4 (7.2-27.3)µg/mL, 10.5 (3.2-12.8) µg/mL, and 0.52 (0.46-0.57), respectively. An exploratory survival analysis showed that the higher HMWR values at admission and the larger decrease in HMWR were associated with a better prognosis after discharge. CONCLUSION: Plasma total APN and HMW-APN values are elevated at the admission for acute HF. Plasma total APN, HMW-APN, and HMWR values decrease following treatment. Higher HMWR at admission and its larger decrease may be the signs of favorable treatment responsiveness in acute HF.

Birth length is a predictor of adiponectin levels in Japanese young children.

BACKGROUND: Adiponectin has been shown to be inversely related to birth weight in schoolchildren and adolescents. However, the available information regarding a relation between birth size and adiponectin in infants and preschoolers is limited. METHODS: A longitudinal study was conducted among healthy Japanese children, and serum adiponectin levels were measured at consecutive visits. The effect of sex, gestational age, birth length, birth weight, or placental weight on adiponectin was analyzed by using a linear mixed model for repeated measures. RESULTS: Eighty-three children were evaluated. The age range at the first visit was 0.07-5.3 years. A total number of 227 measurements were made, 1-12 per subject (median, 3) and the duration of follow-up ranged from 1 day to 2.3 years (median, 1.0 years). The subjects were divided into four groups according to the age at the first visit: (1) 0-2 months (n = 29), (2) 3 months to 1 year (n = 17), (3) 2-3 years (n = 19) and (4) 4-5 years (n = 18). In the multivariate model, birth length (coefficient = 3.94, 95% CI, 0.23-7.65) was an independent predictor of serum adiponectin levels in subjects aged 0-2 months. Gestational age (3.53, 1.14-5.92), birth length (-2.71, -4.90 to -0.53) and placental weight (2.58, 0.86-4.29) were independent predictors of serum adiponectin levels in subjects aged 4-5 years. CONCLUSION: Birth length, not birth weight, is an independent predictor of serum adiponectin levels in Japanese young children.

Determinants of adiponectin levels in patients with chronic systolic heart failure.

Adiponectin, an adipocytokine, is secreted by adipocytes and mediates antihypertrophic and anti-inflammatory effects in the heart. Plasma concentrations of adiponectin are decreased in the presence of obesity, insulin resistance, and obesity-associated conditions such as hypertension and coronary heart disease. However, a paradoxical increase in adiponectin levels is observed in human systolic heart failure (HF). We sought to investigate the determinants of adiponectin levels in patients with chronic systolic HF. Total adiponectin levels were measured in 99 patients with stable HF and a left ventricular (LV) ejection fraction of <40%. The determinants of adiponectin levels on univariate analysis were included in a multivariate linear regression model. At baseline, 62% of the patients were black, 63% were men, the mean age was 60 + or - 13 years, the LV ejection fraction was 21 + or - 9%, and the body mass index was 30.6 + or - 6.7 kg/m(2). The mean adiponectin level was 15.8 + or - 15 microg/ml. Beta-Blocker use, body mass index, and blood urea nitrogen were significant determinants of adiponectin level on multivariate analysis. The LV mass, structure, and LV ejection fraction were not related to adiponectin levels on multivariate analysis. The effect of beta-blocker therapy was most marked in nonobese patients with a body mass index <30 kg/m(2). In conclusion, in patients with chronic systolic HF, beta-blocker therapy correlated with lower adiponectin levels, especially in nonobese patients. This relation should be taken into account when studying the complex role of adiponectin in patients with chronic systolic HF.

Increment and impairment of adiponectin in renal failure.

AIMS: Patients with chronic renal failure are at high risk of cardiovascular diseases. Previous studies in healthy population showed that hypoadiponectinemia was associated with high cardiovascular disease risk. However, plasma adiponectin (APN) levels are increased in renal dysfunction. Therefore, the clinical significance of plasma APN level in patients with moderate renal dysfunction is controversial. The aim of this study was to determine the change of plasma APN levels in a mouse model of renal failure and the loss of vasculo-protective function of APN in the presence of high cystatin C levels. METHODS AND RESULTS: Subtotal (5/6) nephrectomy was performed in APN-knockout (KO) mice and wild-type (WT) mice. The procedure in WT mice resulted in the significant increase of plasma APN and cystatin C levels. The clearance rate of APN was measured by injecting plasma from WT mice into KO mice. The clearance rate was significantly decreased in subtotal nephrectomized KO mice compared with sham-operated KO mice. Adiponectin protein and mRNA levels in adipose tissue were similar to subtotal nephrectomized and sham-operated mice. In cultured endothelial cells, at a high concentration corresponding to renal failure, cystatin C abolished the suppressive effects of APN on tumour necrosis factor alpha-induced expression of monocyte adhesion molecules. CONCLUSION: Plasma APN increases in chronic renal failure, at least in part due to low clearance rate. High concentrations of cystatin C abolish the vasculo-protective effect of APN.

Adiponectin and testosterone in patients with symptoms of late-onset hypogonadism: is there a link?

OBJECTIVES: To examine the correlation between testosterone and adiponectin in symptomatic late-onset hypogonadism (LOH) patients. METHODS: The study included 174 patients (>40 years old) with at least one LOH symptom and an Aging Male Symptoms score >26. The correlation between serum adiponectin levels and various factors was investigated by simple and multiple regression analyses. Serum adiponectin levels before and after testosterone replacement therapy (TRT) in 43 patients with serum free testosterone <11.8 pg/mL were also compared. RESULTS: Serum adiponectin levels increased with increased age (P < 0.01), decreased with increased body mass index (P < 0.01), and increased with increased sex hormone-binding globulin (P < 0.01). Multiple regression analysis revealed that body mass index and sex hormone-binding globulin were factors with an influence on serum adiponectin levels. However, no association between testosterone and adiponectin was found. In the 43 patients receiving TRT, serum adiponectin levels before and after TRT did not differ significantly. CONCLUSIONS: Serum adiponectin is not related to serum testosterone in symptomatic LOH patients, suggesting that TRT in these subjects does not pose a higher risk of inducing a metabolic syndrome.

Adiponectin protects against angiotensin II-induced cardiac fibrosis through activation of PPAR-alpha.

OBJECTIVE: Adiponectin is recognized as an antidiabetic, antiatherosclerotic, and anti-inflammatory protein derived from adipocytes. However, the role of adiponectin in cardiac fibrosis remains uncertain. We herein explore the effects of adiponectin on cardiac fibrosis induced by angiotensin II (Ang II). METHODS AND RESULTS: Wild-type (WT), adiponectin knockout (Adipo-KO), and PPAR-alpha knockout (PPAR-alpha-KO) mice were infused with Ang II at 1.2 mg/kg/d. Severe cardiac fibrosis and left ventricular dysfunction were observed in Ang II-infused Adipo-KO mice compared to WT mice. Adenovirus-mediated adiponectin treatment improved the above phenotypes and the dysregulation of reactive oxygen species (ROS)-related mRNAs in Adipo-KO mice, whereas such amelioration was not observed in PPAR-alpha-KO mice despite adiponectin accumulation in heart tissue. In cultured cardiac fibroblasts, adiponectin improved the reduction of AMP-activated protein kinase (AMPK) activity and elevation of extracellular signal-regulated kinase 1/2 (ERK1/2) activity induced by Ang II. Adiponectin significantly enhanced PPAR-alpha activity, whereas the adiponectin-dependent PPAR-alpha activation was diminished by Compound C, an inhibitor of AMPK. CONCLUSIONS: The present study suggests that adiponectin protects against Ang II-induced cardiac fibrosis possibly through AMPK-dependent PPAR-alpha activation.

Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals.

BACKGROUND: Enlargement of adipocytes from subcutaneous abdominal adipose tissue (SAT), increased intrahepatic lipid content (IHL), intramyocellular lipid content (IMCL), and low circulating adiponectin concentrations are associated with insulin resistance. OBJECTIVE: Because adiponectin increases fat oxidation in skeletal muscle and liver, and the expression of the adiponectin gene in SAT is inversely associated with adipocyte size, we hypothesized that hypoadiponectinemia links hypertrophic obesity with insulin resistance via increased IMCL and IHL. DESIGN: Fifty-three obese Pima Indians with a mean (+/-SD) age of 27 +/- 8 y, body fat of 35 +/- 5%, and normal glucose regulation (normal fasting and 2-h glucose concentration per WHO 1999 criteria) underwent euglycemic-hyperinsulinemic clamp, biopsies of SAT and vastus lateralis muscle, and magnetic resonance imaging of the abdomen. RESULTS: Adipocyte diameter (AD) correlated positively with body fat (P < 0.0001) and IHL (estimated from magnetic resonance imaging intensity of liver; P = 0.047). No association was found between AD and plasma adiponectin or IMCL. Plasma adiponectin negatively correlated with type II IMCL (IIA, P = 0.004; IIX, P = 0.009) or IHL (P = 0.02). In a multivariate analysis, plasma adiponectin, AD, and visceral adipose tissue (VAT) independently predicted IHL. Low insulin-mediated glucose disposal was associated with low plasma adiponectin (P = 0.02) and high IHL (P = 0.0003), SAT (P = 0.02), and VAT (P = 0.04). High IHL was the only predictor of reduced insulin-mediated suppression of hepatic glucose production (P = 0.02) and the only independent predictor of insulin-mediated glucose disposal in a multivariate analysis. CONCLUSIONS: Increased lipid content in the liver may independently link hypoadiponectinemia, hypertrophic obesity, and increased visceral adiposity with peripheral and hepatic insulin resistance.

URB is abundantly expressed in adipose tissue and dysregulated in obesity.

Dysregulated production of adipocytokines in obesity is involved in the development of metabolic syndrome. URB/DRO1 contains N-terminal signal sequence and is thought to play a role in apoptosis of tumor cells. In the present study, we investigated the expression pattern of URB mRNA in adipose tissue and secretion from cultured adipocytes. In human and mouse, URB mRNA was predominantly expressed in adipose tissue and was downregulated in obese mouse models, such as ob/ob, KKAy, and diet-induced obese mice. In 3T3L1 adipocytes, insulin, TNF-alpha, H(2)O(2) and hypoxia decreased URB mRNA level. This regulation was similar to that for adiponectin and opposite to MCP-1. URB protein was secreted in media of URB cDNA-stably transfected cells and endogenous URB was detected in media of cultured human adipocytes. In conclusion, the expression pattern of URB suggests its role in obesity and the results suggest that URB is secreted, at least in part, from adipocytes.

Nocturnal reduction in circulating adiponectin concentrations related to hypoxic stress in severe obstructive sleep apnea-hypopnea syndrome.

Previous reports demonstrated that adiponectin has antiatherosclerotic properties. Obstructive sleep apnea-hypopnea syndrome (OSAHS) is reported to exacerbate atherosclerotic diseases. We investigated nocturnal alternation of serum adiponectin levels before sleep and after wake-up in OSAHS patients and the effect of sustained hypoxia on adiponectin in vivo and in vitro. We measured serum adiponectin concentrations in 75 OSAHS patients and 18 control subjects before sleep and after wake-up and examined the effect of one-night nasal continuous positive airway pressure (nCPAP) on adiponectin in 24 severe OSAHS patients. We investigated the effects of hypoxia on adiponectin in mice and cultured adipocytes with a sustained hypoxia model. Circulating adiponectin levels before sleep and after wake-up were lower in severe OSAHS patients than in control subjects [before sleep: 5.9 +/- 2.9 vs. 8.8 +/- 5.6 microg/ml (P < 0.05); after wake-up: 5.2 +/- 2.6 vs. 8.5 +/- 5.5 microg/ml (P < 0.01), respectively; means +/- SD]. Serum adiponectin levels diminished significantly during sleep in severe OSAHS patients (P < 0.0001), but one-night nCPAP improved the drop in serum adiponectin levels [-18.4 +/- 13.4% vs. -10.4 +/- 12.4% (P < 0.05)]. In C57BL/6J mice and 3T3-L1 adipocytes, hypoxic exposure decreased adiponectin concentrations by inhibiting adiponectin regulatory mechanisms at secretion and transcriptional levels. The present study demonstrates nocturnal reduction in circulating adiponectin levels in severe OSAHS. Our experimental studies showed that hypoxic stress induced adiponectin dysregulation at transcriptional and posttranscriptional levels. Hypoxic stress is, at least partly, responsible for the reduction of serum adiponectin in severe OSAHS. Nocturnal reduction in adiponectin in severe OSAHS may be an important risk for cardiovascular events or other OSAHS-related diseases during sleep.

Clinical significance of high-molecular weight form of adiponectin in male patients with coronary artery disease.

BACKGROUND: It has been reported previously that the measurement of plasma total adiponectin level is clinically useful to estimate the risk of coronary artery disease (CAD). Here, the relevance of high molecular weight (HMW) adiponectin with risk factors for atherosclerosis is investigated METHODS AND RESULTS: A total of 186 consecutive male CAD patients participated in the study and were categorized into quartiles based on their total adiponectin level. The interquartile cut-off points were 4.0, 5.5 and 7.0 microg/ml. The HMW adiponectin levels were significantly lower in the quartile of lower total adiponectin levels both in non-diabetic and diabetic patients. In contrast, low molecular weight adiponectin levels (which were calculated as the Total - HMW) were constant. In univariate analysis, total adiponectin correlated negatively with body mass index and hemoglobin (Hb) A1c, and HMW adiponectin correlated negatively with HbA1c in non-diabetic patients. On the other hand, total and HMW adiponectin correlated positively with high-density lipoprotein-cholesterol (HDL-C) in diabetic patients. Multiple regression analysis revealed that HMW adiponectin correlated negatively with HbA1c in non-diabetic patients, and total and HMW adiponectin correlated positively with HDL-C in diabetic patients. CONCLUSIONS: Change in the HMW isoform reflects a change in total adiponectin level. Measurement of total and HMW adiponectin were equally useful in assessing metabolic risk in CAD patients.

Adiponectin accumulates in myocardial tissue that has been damaged by ischemia-reperfusion injury via leakage from the vascular compartment.

OBJECTIVES: Adiponectin, a circulating adipocyte-derived hormone, exerts beneficial actions on hearts subjected to ischemia-reperfusion injury. Adiponectin exists in plasma as three different oligomeric forms: trimer, hexamer and high molecular weight. This study investigated the expression and myocardial accumulation of adiponectin in a murine model of ischemia-reperfusion injury. METHODS: Wild-type and adiponectin deficient mice were subjected to left anterior descending artery ligation followed by reperfusion. Plasma adiponectin levels were analyzed by ELISA and adiponectin in heart was determined by immunohistochemical, Western blot and real-time PCR analyses. RESULTS: Plasma adiponectin levels declined after myocardial ischemia-reperfusion injury due to reductions in high molecular weight and, to a lesser extent, trimer and hexamer isoforms. Adiponectin protein was detected in injured but not sham-operated heart, and this was accompanied by a negligible increase in adiponectin transcript in the myocardium. Systemic delivery of adiponectin to adiponectin knockout (APN-KO) mice led to the accumulation of adiponectin in ischemia-reperfusion-injured, but not-uninjured hearts at levels comparable to wild-type suggesting that cardiac expression of adiponectin does not appreciably contribute to its accumulation in the infarcted heart. The serum half-life of adiponectin was 7.4+/-0.3 h in ischemia-reperfusion and 9.7+/-0.5 h in sham-operated mice (P>0.05), whereas the half-life of adiponectin in the damaged heart was 26.9+/-2.2 h (P<0.05). CONCLUSIONS: These data show that adiponectin accumulates in the heart following ischemic damage primarily through leakage from the vascular compartment, and that adiponectin has a longer half-life in damaged heart tissue than in plasma.