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PubMed2005

Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin.

Obese (fa/fa) Zucker rat is a spontaneous genetic obesity model and, by comparison with lean Zucker rat, exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia. The aim of this study was to examine the physiological difference concerning adiponectin between obese (fa/fa) Zucker rats and control lean Zucker rats. We therefore measured plasma adiponectin level and analyzed adiponectin and adiponectin receptor 1 mRNA expression in retroperitoneal white adipose tissue (RT WAT), brown adipose tissue (BAT), liver, and soleus muscle. We also examined the tissue mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR alpha), PPAR delta, and PPAR gamma, which regulate adiponectin expression sensitivity to a PPAR gamma agonist shown by brown adipocytes from obese (fa/fa) Zucker rats and lean Zucker rats, by measuring adiponectin release from these cells. Plasma adiponectin levels of obese (fa/fa) Zucker rats were significantly higher than those of lean Zucker rats. Adiponectin mRNA expression levels in RT WAT were lower in obese (fa/fa) Zucker rats than in lean Zucker rats, but those in BAT were higher. Adiponectin receptor 1 expression levels in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats were lower than in lean Zucker rats. The expression level of PPAR alpha, PPAR delta, and PPAR gamma in BAT was lower in obese (fa/fa) Zucker rats than in lean Zucker rats. Moreover, the PPAR gamma agonist increased adiponectin release only from the brown adipocytes isolated from lean Zucker rats. It is the conclusive difference between obese (fa/fa) Zucker rats and lean Zucker rats that plasma adiponectin levels of obese (fa/fa) Zucker rats are significantly higher than those of lean Zucker rats. Moreover, we clarified that mRNA expression level of adiponectin receptor 1 in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats is low despite high plasma adiponectin level, and low expression of PPARs in BAT leads to less sensibility of adiponectin release from brown adipocytes to a PPAR gamma agonist in obese (fa/fa) Zucker rats.

Adipocytes↗
PubMed2002

Adiponectin: a link between excess adiposity and associated comorbidities?

Adiponectin is a novel polypeptide that is highly specific to adipose tissue. In contrast to other adipocytokines, adiponectin levels are decreased in obesity and associated comorbidities, such as type 2 diabetes. Decreased expression of adiponectin is correlated with insulin resistance. It has been suggested that several agents, such as tumor necrosis factor alpha, could mediate their effects on insulin metabolism through modulating adiponectin secretion from adipocytes. The mechanisms for the development of atherosclerotic vascular disease in obese individuals are largely unknown. Several findings support the interesting hypothesis that adiponectin could be a link between obesity and related atherosclerosis. First, adiponectin levels are lower in patients with coronary artery disease. Second, adiponectin modulates endothelial function and has an inhibitory effect on vascular smooth muscle cell proliferation. Moreover, adiponectin is accumulated more preferably to the injured vascular wall than intact vessels and has been shown to suppress macrophage-to-foam cell transformation. Adiponectin may also be involved in the modulation of inflammation. Thiazolidinediones, antiatherogenic and other effects have been explained by their direct enhancing effect on adiponectin. In conclusion, adiponectin has anti-inflammatory and antiatherogeneic effects as well as multiple beneficial effects on metabolism. Therefore it is not a surprise that adiponectin therapy has been tested in animal models of obesity, and it has been shown to ameliorate hyperglycemia and hyperinsulinemia without inducing weight gain or even inducing weight loss in some studies. Unlike agents that exert their effects centrally, adiponectin's effects seem to be peripherally mediated. The evidence of an association between adiponectin and the metabolic and cardiovascular complications of obesity is growing all the time.

Adipocytes↗
PubMed2005

Interaction of low serum adiponectin levels and smoking on coronary stenosis in Japanese men.

BACKGROUND: The relationship between serum adiponectin levels and coronary stenosis and the interaction of low serum adiponectin levels and smoking on coronary stenosis have not been clarified. METHODS: We conducted a hospital-based case-control study to examine serum adiponectin levels and smoking in 86 male patients with coronary stenosis and 145 male controls, using multiple logistic regression analyses. Serum adiponectin levels were grouped into quartiles for the analysis of the relationship between serum adiponectin levels and coronary stenosis, and into dichotomy for the analysis of the interaction of low serum adiponectin levels and smoking status. RESULTS: Decreasing serum adiponectin levels were significantly associated with increased risk of coronary stenosis in a dose-dependent manner. As for the interaction of low serum adiponectin levels and smoking on coronary stenosis, adjusted odds ratios were 14.00 (95% Confidence Interval 5.45-37.48) among ever-smokers with low serum adiponectin levels, 3.84 (95% CI: 1.44-10.21) among ever-smokers with high serum adiponectin levels and 3.79 (95% CI: 1.38-10.45) among never-smokers with low serum adiponectin levels, compared with the reference group of never-smokers with high serum adiponectin levels. CONCLUSIONS: The interaction of low serum adiponectin levels and smoking on coronary stenosis was likely to be a synergic effect. This study suggests that the combination of low serum adiponectin levels and smoking is the most useful predictor for coronary stenosis among Japanese men.

Adiponectin↗
PubMed2005

Corticosteroid-binding globulin affects the relationship between circulating adiponectin and cortisol in men and women.

Inflammatory pathways are increasingly recognized to be tightly associated with insulin resistance in humans. The promoter region of the adiponectin gene--Apm1--encompasses consensus sequences for glucocorticosteroid receptor responsive element. Dexamethasone induced downregulation of adiponectin secretion in vitro, whereas prednisolone administration increased circulating adiponectin concentrations. As previous studies have demonstrated an inverse relationship between corticosteroid-binding globulin (CBG), body mass index, and insulin resistance, we studied whether CBG could explain cortisol-to-adiponectin relationship. One hundred twenty-two healthy subjects were enrolled in a cross-sectional study. Plasma CBG and serum cortisol concentration were measured by radioimmunoassay. The cortisol-to-CBG ratio was used to calculate free cortisol. An RIA kit (Linco Research, St Louis, MO) was used to measure adiponectin levels. Insulin resistance was calculated using the homeostatis model of assessment (HOMA) value. Circulating adiponectin was associated with serum CBG ( r = 0.38, P < .00001), both in men ( r = 0.26, P = .03, n = 79) and women ( r = 0.48, P = .003, n = 43), and with insulin resistance (HOMA index) ( r = -0.30, P < .0001) in both. Free cortisol correlated negatively with adiponectin only in women ( r = -0.32, P = .04), but not in men ( r = 0.01, P = .89). Serum CBG concentration was significantly lower among men in the lowest quartile of adiponectin when compared with the remaining subjects (37.3 +/- 5.7 vs 40.6 +/- 5.1, P = .016), whereas men in the highest quartile of adiponectin showed significantly increased free cortisol index (14.2 +/- 3.3 vs 12.2 +/- 3.1, P = .039). Women in the lowest quartile of adiponectin also displayed significantly lower CBG concentration than that present in the remaining subjects (38.6 +/- 6.9 vs 44.4 +/- 5.5, P = .016), whereas free cortisol index was not significantly different across adiponectin quartiles ( P = .1). In a stepwise regression analysis, body mass index ( P = .0011), CBG ( P = .0047), and sex ( P = .04) contributed to 15%, 8%, and 3%, respectively, of adiponectin variance. Using CBG as dependent variable, both adiponectin ( P = .0002) and fasting cortisol ( P = .019) contributed to 14% and 4%, respectively, of CBG variance. In summary, circulating adiponectin, CBG concentration, and fasting cortisol were significantly interrelated in healthy subjects. A significant sexual dimorphism exists in this association.

Adiponectin↗
PubMed2004

Identification of influencing variables on adiponectin serum levels in diabetes mellitus type 1 and type 2.

BACKGROUND: Adiponectin represents an adipocyte-specific secretory protein that has been discussed recently as candidate gene and promising new drug target to restore insulin sensitivity in diabetes mellitus type 2. AIM: The aim of the present study was to define influencing variables on adiponectin serum levels in a large cohort of caucasian patients with type 1/type 2 diabetes and healthy controls. Additionally, adiponectin gene polymorphisms (Tyr111His and Gly15Gly) were investigated for possible associations with adiponectin serum levels. METHODS: Adiponectin serum concentrations were measured in a metabolically well characterized cohort of 892 caucasian patients (556 with type 2 diabetes, 118 with type 1 diabetes, 218 controls) by ELISA. Gene polymorphisms were determined by PCR-based RFLP. RESULTS: 1) Adiponectin values are dependent on gender with higher levels in diabetic females than in diabetic males. This gender-specific effect was only restricted to patients with diabetes and cannot be observed in controls. 2) In contrast to previous studies, the presence of diabetes does not influence adiponectin serum levels after correction for BMI. In addition, age has no influence on adiponectin levels. 3) Adiponectin levels are dependent on renal function at a creatinine clearance < 45 ml/min. 4) Regression analysis showed a significant, but only weak correlation between BMI and adiponectin in patients with diabetes mellitus type 2 (r = 0.47) and type 1 (r = 0.57). 5) Adiponectin gene polymorphisms (Tyr111His and Gly15Gly) do not influence adiponectin levels. CONCLUSIONS: Adiponectin serum concentrations can only be interpreted after careful correction for gender and renal function, whereas the genetic variants Tyr11His and Gly15Gly do not seem to play a role. The correlation between BMI and adiponectin was weaker than expected in diabetic patients.

Adiponectin↗
PubMed2004

Correlations between umbilical and maternal serum adiponectin levels and neonatal birthweights.

OBJECTIVE: To measure adiponectin levels in maternal serum and umbilical cord serum at delivery, and examine whether or not there are correlations between adiponectin levels and neonatal birthweights, maternal body weights and body mass indexes. STUDY DESIGN: The study included 84 healthy mothers who had given birth to healthy neonates. Adiponectin levels in maternal serum and umbilical cord serum were determined by radioimmunoassay and compared. RESULTS: The ranges of adiponectin levels for umbilical cord serum and maternal serum were 22.7-78.4 microg/ml and 4.0-43.3 microg/ml, respectively. Umbilical serum adiponectin levels (46.9 +/- 1.2 microg/ml) were significantly higher than maternal serum adiponectin levels (16.1 +/- 0.8 micro g/ml) (p < 0.001). No correlation was found between the adiponectin levels in maternal serum and those in umbilical cord serum (r = 0.158, p = 0.151). Umbilical serum adiponectin levels were significantly correlated with both neonatal birthweights (r = 0.454, p < 0.001) and gestational ages at birth (r = 0.295, p = 0.006), but not with maternal serum adiponectin levels. Maternal serum adiponectin levels were only negatively correlated to maternal weights and body mass index at delivery (r = 0.288, p = 0.008; r = 0.372, p < 0.001). CONCLUSION: The levels of adiponectin were higher in umbilical cord serum than in maternal serum. Moreover, the adiponectin levels in umbilical cord serum were found to correlate positively with neonatal birthweights. Therefore, fetal adiponectin, not maternal serum adiponectin, may be involved in fetal development during late pregnancy.

Adiponectin↗
PubMed2005

Plasma, urine, and renal expression of adiponectin in human systemic lupus erythematosus.

BACKGROUND: Adiponectin is an adipocyte-derived cytokine that has anti-inflammatory properties. A preliminary proteomic evaluation of urine for biomarkers of systemic lupus erythematosus (SLE) nephritis demonstrated high levels of adiponectin in SLE urine. This prompted investigation of adiponectin expression in human SLE. METHODS: Adiponectin was measured by enzyme-linked immunosorbent assay (ELISA) in the urine and plasma of a clinically well-characterized SLE cohort, with renal and nonrenal SLE being followed in a prospective longitudinal study to identify risk factors for SLE flare. Renal adiponectin expression was assessed by immunohistochemical analysis of kidney biopsies from SLE nephritis patients. RESULTS: Cross-sectional testing showed that plasma adiponectin levels were higher in patients with renal SLE flare than normal controls or patients with nonrenal SLE flare, after accounting for race and body mass index. Urine adiponectin levels increased significantly with renal flare, but not nonrenal SLE flare. Longitudinal testing revealed that the urine adiponectin increase began in the 2 months prior to renal flare. Urine adiponectin correlated with plasma levels and magnitude of proteinuria, and to a lesser extent serum creatinine. Plasma adiponectin levels were independent of renal function and proteinuria. In kidney biopsies, adiponectin was found on endothelial surfaces in normal and SLE kidneys, and on podocytes and in the tubules of SLE kidneys. CONCLUSION: Plasma adiponectin levels are increased in patients with renal SLE compared to healthy controls and patients with nonrenal SLE. During renal but not nonrenal SLE flare, urine adiponectin levels increase significantly. Urine adiponectin may be a biomarker of renal SLE flare.

Adiponectin↗
PubMed2006

Chronic ethanol feeding to rats decreases adiponectin secretion by subcutaneous adipocytes.

Chronic ethanol feeding to mice and rats decreases serum adiponectin concentration and adiponectin treatment attenuates chronic ethanol-induced liver injury. Although it is clear that lowered adiponectin has pathophysiological importance, the mechanisms by which chronic ethanol decreases adiponectin are not known. Here, we have investigated the impact of chronic ethanol feeding on adiponectin expression and secretion by adipose tissue. Rats were fed a 36% Lieber-DeCarli ethanol-containing liquid diet or pair-fed control diet for 4 wk. Chronic ethanol feeding decreased adiponectin mRNA but had no effect on adiponectin protein in subcutaneous adipose tissue. Chronic ethanol feeding also reduced adiponectin secretion by isolated subcutaneous and retroperitoneal adipocytes despite the maintenance of equivalent intracellular concentrations of adiponectin between subcutaneous adipocytes from ethanol- and pair-fed rats. Treatment with brefeldin A suppressed adiponectin secretion by subcutaneous adipocytes from pair-fed rats but had little effect after ethanol feeding. In subcutaneous adipocytes from pair-fed rats, adiponectin was enriched in endoplasmic reticulum (ER)/Golgi relative to plasma membrane; however, after chronic ethanol feeding, adiponectin was equally distributed between plasma membrane and ER/Golgi fractions. In conclusion, chronic ethanol feeding impaired adiponectin secretion by subcutaneous and retroperitoneal adipocytes; impaired secretion likely contributes to decreased adiponectin concentrations after chronic ethanol feeding.

Adipocytes↗
PubMed2006

Salivary gland epithelial cells: a new source of the immunoregulatory hormone adiponectin.

OBJECTIVE: Adiponectin is an adipocytokine that displays insulin-sensitizing and immunoregulatory properties. Adipocyte development in association with fibrosis is frequently detected in primary Sjögren's syndrome lesions, connoting a healing process. The aim of this study was to examine the expression of adiponectin in minor salivary gland biopsy specimens obtained from patients with primary SS and controls. METHODS: The expression of adiponectin in minor salivary gland biopsy specimens and in long-term-cultured non-neoplastic salivary gland epithelial cell (SGEC) lines obtained from patients with primary SS and control subjects was examined, using immunohistochemistry and immunoblotting, respectively. The expression of adiponectin, adiponectin receptor 1 (AdipoR1), and AdipoR2 messenger RNA (mRNA) by SGECs was investigated by reverse transcription-polymerase chain reaction. RESULTS: Immunohistochemical analysis for adiponectin revealed positive staining of adipocytes from primary SS lesions as well as ductal epithelial cells from both patients with primary SS and controls. All of the SGEC lines tested were shown to express adiponectin, AdipoR1, and AdipoR2 mRNA, whereas adiponectin protein expression was detected by immunoblotting in SGECs from patients with primary SS but not in those from controls. The analysis of concentrated culture supernatants also revealed increased adiponectin expression by SGECs from patients with SS compared with controls. CONCLUSION: Our findings provide novel evidence that adiponectin is produced by SGECs. The high constitutive expression of adiponectin by SGECs from patients with primary SS is likely attributable to aberrant activation of these cells. Although the significance of adiponectin expression remains unknown, it is possible that adiponectin functions in an autocrine manner, as suggested by concurrent expression of the relevant receptors.

Adiponectin↗
PubMed2006

Adiponectin attenuates allergen-induced airway inflammation and hyperresponsiveness in mice.

BACKGROUND: Epidemiologic data indicate an increased incidence of asthma in the obese. OBJECTIVE: Because serum levels of the insulin-sensitizing and anti-inflammatory adipokine adiponectin are reduced in obese individuals, we sought to determine whether exogenous adiponectin can attenuate allergic airway responses. METHODS: We sensitized and challenged BALB/cJ mice with ovalbumin (OVA). Alzet micro-osmotic pumps were implanted in the mice to deliver continuous infusions of buffer or adiponectin (1.0 microg/g/d), which resulted in an approximate 60% increase in serum adiponectin levels. Two days later, mice were challenged with aerosolized saline or OVA once per day for 3 days. Mice were examined 24 hours after the last challenge. RESULTS: OVA challenge increased airway responsiveness to intravenous methacholine, bronchoalveolar lavage fluid cells, and T(H)2 cytokine levels. Importantly, each of these responses to OVA was reduced in adiponectin- versus buffer-treated mice. OVA challenge caused a 30% reduction in serum adiponectin levels and a corresponding decrease in adipose tissue adiponectin mRNA expression. OVA challenge also decreased pulmonary mRNA expression of each of 3 proposed adiponectin-binding proteins, adiponectin receptor 1, adiponectin receptor 2, and T-cadherin. CONCLUSION: Our results indicate that serum adiponectin is reduced during pulmonary allergic reactions and that adiponectin attenuates allergic airway inflammation and airway hyperresponsiveness in mice. CLINICAL IMPLICATIONS: The data suggest that adiponectin might play a role in the relationship between obesity and asthma.

Adiponectin↗
PubMed2006

Identification of amino-terminal region of adiponectin as a physiologically functional domain.

Adiponectin is an abundant adipose-specific protein, which acts as an anti-diabetic, anti-atherogenic, and anti-inflammatory adipokine. Although recent advances in the field of adiponectin have been made by the identification of adiponectin receptors and by the understanding about relationship between its multimerization and functions, detailed molecular background remains unclear. Our established anti-human adiponectin antibodies, ANOC 9103 and ANOC 9104, blocked some adiponectin functions such as the growth inhibition of B-lymphocytes on stromal cells and the inhibition of acetylated LDL uptake in macrophages, suggesting that they may recognize important functional regions of adiponectin. As a result of epitope mapping based on the ability to bind to the deleted adiponectin mutants, we identified that these antibodies recognize amino-terminal region of adiponectin before the beginning of the collagen-like domain. Notably, a peptide fragment (DQETTTQGPGVLLPLPKGACTGWMA) corresponding to amino acid residues 17-41 of human adiponectin could bind to restricted types of cells and block adiponectin-induced cyclooxygenase-2 gene expression and prostaglandin E2 production in MS-5 stromal cells. Moreover, the deletion of its amino-terminal region reduced the abilities to inhibit not only collagen-induced platelet aggregation but also diet-induced hepatic steatosis. These data indicate that amino-terminal region of adiponectin is a physiologically functional domain and that a novel receptor, which recognizes amino-terminal region of adiponectin, may exist on some types of cells. Further investigations will contribute to the understanding of molecular mechanisms about adiponectin functions as well as to the designing of novel strategies for the treatment of patients with insulin-resistance, vascular dysfunction, and chronic inflammation.

Adiponectin↗
PubMed2005

Adiponectin expression in humans is dependent on differentiation of adipocytes and down-regulated by humoral serum components of high molecular weight.

Adiponectin is an adipocytokine with profound anti-diabetic and anti-atherogenic effects. Even though adiponectin expression is restricted to adipocytes, serum levels are paradoxically decreased in obesity. We characterized how adiponectin expression and regulation relates to adipocyte differentiation in a human adipocyte cell culture model. Adiponectin was not expressed by human preadipocytes. Differentiation into adipocytes was necessary to induce an increasing expression of adiponectin (359 +/- 64-fold, P < 0.001) in parallel to an increasing expression of adipocyte differentiation markers. Adiponectin protein synthesis and secretion occurred specifically in mature adipocytes and may thus serve as a distinctive marker of adipocyte differentiation. Addition of serum during the course of differentiation as well as acutely to mature adipocytes significantly and concentration-dependently suppressed adiponectin to almost non-detectable levels (to 9.8 +/- 0.03%, P = 0.0043), suggesting a strong humoral serum component of adiponectin down-regulation. This serum component is present in both obese and lean individuals with a tendency to a stronger effect in obese men and women. Separation by molecular size suggests that higher molecular weight (>30 kDa) fractions exert inhibition of adiponectin. Withdrawal of adipogenic ingredients from the culture medium also resulted in a decrease of adiponectin expression and secretion to 62.01 +/- 0.09% and 70.86 +/- 0.05%, respectively. We identified insulin as a critical component to maintain adiponectin expression with a down-regulation to 61.6 +/- 0.1% (P = 0.0011) in the absence of insulin. These dynamic changes of adiponectin expression and regulation with adipocyte differentiation are of physiological interest in the light of the paradoxical decrease of adiponectin levels and the continuous recruitment of preadipocytes for differentiation in obesity.

Adipocytes↗
PubMed2006

Plasma adiponectin is related to other cardiovascular risk factors in nondiabetic Korean men with CAD, independent of adiposity and cigarette smoking: cross-sectional analysis.

BACKGROUND: Circulating adiponectins have multiple protective roles as anti-diabetic, anti-atherosclerotic, and anti-inflammatory factors. We examined the relationship between plasma adiponectin concentration and other cardiovascular risk in nondiabetic coronary artery disease (CAD) men and the relationship can be maintained even after adjusted for major environmental factors that contribute to adiponectin concentrations. METHODS: Nondiabetic CAD men (n=613) were 31-70 y and had body mass index (BMI) of 18.5-29.9 kg/m2. RESULTS: Circulating adiponectins positively correlated with age and negatively with BMI, waist circumference and % body fat (p-values of all <0.001). Plasma adiponectin concentrations were higher in never-smokers (5.07+/-0.30 microg/ml) than current (4.15+/-0.12 microg/ml) and ex-smokers (3.75+/-0.20 microg/ml) both before and after adjusted for age and adiposity (p=0.002 and p=0.008, respectively), however they were not significantly different according to alcohol drinking status. After adjusted for age, adiposity and cigarette smoking, plasma adiponectin still have positive correlations with HDL cholesterol, apolipoprotein AI and LDL particle size, and inversely with fasting triglyceride, atherogenic index, insulin resistance and C-reactive protein (CRP). However there was no significant relationships between adiponectin and apolipoprotein B, total cholesterol or LDL cholesterol. In subset analysis by tertile adiponectin concentrations (lowest: <2.92, moderate: 2.92 or=4.75 microg/ml), 'moderate' and 'highest' adiponectin groups had lower triglyceride (p<0.001), lower atherogenic index (p=0.001), lower fasting insulin (p=0.004), lower insulin resistance (p=0.001), lower CRP (p=0.001), higher HDL cholesterol (p<0.001), higher apolipoprotein AI (p=0.005) and higher LDL particle size (p<0.001) as compared with 'lowest' adiponectin group when adjusted for age, adiposity and cigarette smoking. Platelets were lower in 'highest' adiponectin groups as compared with 'lowest' and 'moderate' adiponectin group after the adjustment. However, there was no significant difference in total cholesterol (p=0.145), LDL cholesterol (p=0.145), apolipoprotein B (p=0.222) and fasting glucose (p=0.157). CONCLUSION: An increase of adiponectin concentrations or the maintenance of higher concentration may be negatively associated with cardiovascular risk factors in nondiabetic CAD male patients, independent of adiposity and smoking status.

Adiponectin↗
PubMed2006

Increased adiponectin is negatively linked to the local inflammatory process in patients with rheumatoid arthritis.

Adiponectin has been shown to exert insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties in metabolic diseases. It has been suggested that adiponectin may play a role in rheumatoid arthritis (RA). To assess adiponectin in serum and synovial fluid from patients with RA and osteoarthritis (OA), and in serum from healthy controls. Adiponectin and CRP levels were analyzed by ELISA. The clinical activity of RA patients was assessed according to the 28 joint count Disease Activity Score. Synovial fluid adiponectin was significantly higher in RA than in OA patients (p<0.001). Adiponectin was negatively associated with the leukocyte count in RA synovial fluid (r=-0.45, p<0.05). Serum adiponectin was higher in RA compared to healthy controls (p<0.02), however comparable to OA patients. Serum adiponectin was higher than in synovial fluid in both diseases (p<0.001). In general, women had higher adiponectin levels than men. Adiponectin was not related to age, disease duration, body mass index, or disease activity of RA patients. Adiponectin is decreased in synovial fluid compared to serum indicating that peripheral fat stores are major producers of adiponectin into the blood stream. However, increased synovial fluid adiponectin in RA patients may counterpart the local inflammatory process.

Adiponectin↗
PubMed2004

Serum adiponectin levels in adult growth hormone deficiency and acromegaly.

Atherosclerosis and insulin resistance are common complications of adult growth hormone deficiency (GHD) and acromegaly. Circulating adiponectin, an adipocyte-derived protein, has both anti-atherogenic and insulin-sensitising effects. In this study, we measured serum adiponectin levels in patients with either adult GHD or acromegaly to clarify the impact of GH secretory states on the regulation of serum adiponectin levels. Serum adiponectin level was measured by radioimmunoassay in 32 patients with adult GHD, 49 patients with acromegaly and 25 normal subjects. The relationships between adiponectin and insulin sensitivity index assessed as quantitative insulin sensitivity check index (QUICKI), BMI, and serum GH and IGF-I levels were then investigated. The values of QUICKI were significantly lower in patients with acromegaly or adult GHD compared to normal subjects (0.33 +/- 0.03, P < 0.01, 0.35 +/- 0.04, P < 0.05 and 0.36 +/- 0.01, respectively). While patients with adult GHD had significantly lower serum adiponectin levels than patients with acromegaly (6.5 +/- 3.9, 9.2 +/- 5.0, P < 0.01) these levels were not significantly different from those found in normal subjects (7.8 +/- 4.3 mug/ml). There was an inverse correlation between serum adiponectin levels and BMI in both patient groups (GHD r = -0.39, P < 0.05; Acromegaly r = -0.35, P < 0.05). However, serum adiponectin levels correlated positively with QUICKI (R(s) = 0.37, P < 0.05) only in patients with adult GHD. In patients with acromegaly, the levels of circulating adiponectin showed an inverse correlation with serum IGF-I levels (R(s) = -0.34, P < 0.05), but not with basal GH levels. These results demonstrate that adiponectin levels are significantly lower in patients with adult GHD than in patients with acromegaly. Adiponectin levels are similar in patients with GHD and healthy controls, whereas in patients with acromegaly, insulin resistance appears to be not closely related to adiponectin levels compared with BMI. The different relationship between adiponectin and QUICKI observed in the adult GHD and acromegaly groups presumably reflects differences in the mechanisms of insulin resistance under states of GH deficiency or excess.

Acromegaly↗
PubMed2006

Circulating concentrations of adiponectin, an endogenous lipopolysaccharide neutralizing protein, decrease in rats with polymicrobial sepsis.

BACKGROUND: Adiponectin is an anti-inflammatory cytokine that is specifically and abundantly produced by adipocytes as a secretory protein. A direct interaction between adiponectin and lipopolysaccharide (LPS) is not fully understood. To elucidate the effects of adiponectin on LPS, we first investigated interactions between recombinant adiponectin and LPS. MATERIALS AND METHODS: Various concentrations of LPS (50, 500, and 5000 pg/ml) and recombinant adiponectin (1, 10, and 100 microg/ml) were incubated for 1 h. The limulus amoebocyte lysate (LAL) activities in the mixture were measured. Interactions between adiponectin (100 microg/ml) and LPS (100 and 300 microg/ml) were also analyzed in Western blotting. Next, we determined plasma adiponectin, tumor necrosis factor-alpha (TNF-alpha), and endotoxin levels at 1.5, 3, and 24 h after onsets of rodent polymicrobial sepsis induced by cecal ligation and puncture (CLP). RESULTS: The incubation with adiponectin significantly and dose-dependently suppressed LAL activity in the mixture compared to control. Western blotting revealed that adiponectin incubated with LPS shifted to a higher mass. In the animal model of sepsis, both plasma endotoxin and TNF-alpha levels after CLP gradually increased and were significantly higher at 3, 24 h compared to those after sham operation. On the contrary, plasma adiponectin levels after CLP gradually decreased and were significantly lower at 3, 24 h compared to those after sham operation. Plasma adiponectin levels were negatively correlated with plasma endotoxin levels (r = -0.77, P < 0.01). CONCLUSIONS: Our results indicate that adiponectin might neutralize LPS in vitro and diminish LPS activity in rats with polymicrobial sepsis. These findings suggest that the anti-inflammatory effects of adiponectin are in part likely because of neutralization of LPS activity.

Adiponectin↗
PubMed2006

High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects.

OBJECTIVE: Our objective was to test the effect of biliopancreatic diversion (BDP) in adiponectin multimerization. Adiponectin, the major protein secreted by adipose tissue, circulates in plasma in different isoforms. The most clinically relevant oligomers are high-molecular weight (HMW) multimers and low-molecular weight (LMW) trimers. Contrasting data on the effect of weight loss on adiponectin isoforms have been reported. RESEARCH METHODS AND PROCEDURES: We measured total plasma adiponectin and HMW and LMW adiponectin oligomers (by Western blot analysis) before and 1 month after BPD, in 18 severely obese subjects. RESULTS: One month after BPD, body weight decreased approximately 11%. Total adiponectin showed significant increase after BPD. In addition, we found a significant increase in HMW (percentage) adiponectin oligomers. We found a significant inverse correlation between HMW (percentage) and BMI before and after BPD. Homeostasis model of assessment-insulin resistance decreased significantly after the BPD, without any significant correlation with total serum adiponectin and adiponectin oligomers. DISCUSSION: A moderate weight loss after BPD increases total and HMW adiponectin oligomers. The significant correlation between BMI and HMW (percentage) adiponectin oligomers but not between BMI and total adiponectin might indicate a role of body fat mass in regulation of adiponectin multimerization. These data suggest that HMW oligomers represent a very sensitive parameter to short-term BMI changes after BPD.

Adiponectin↗
PubMed2003

Adiponectin stimulates production of nitric oxide in vascular endothelial cells.

Adiponectin is secreted by adipose cells and mimics many metabolic actions of insulin. However, mechanisms by which adiponectin acts are poorly understood. The vascular action of insulin to stimulate endothelial production of nitric oxide (NO), leading to vasodilation and increased blood flow is an important component of insulin-stimulated whole body glucose utilization. Therefore, we hypothesized that adiponectin may also stimulate production of NO in endothelium. Bovine aortic endothelial cells in primary culture loaded with the NO-specific fluorescent dye 4,5-diaminofluorescein diacetate (DAF-2 DA) were treated with lysophosphatidic acid (LPA) (a calcium-releasing agonist) or adiponectin (10 microg/ml bacterially produced full-length adiponectin). LPA treatment increased production of NO by approximately 4-fold. Interestingly, adiponectin treatment significantly increased production of NO by approximately 3-fold. Preincubation of cells with wortmannin (phosphatidylinositol 3-kinase inhibitor) blocked only adiponectin- but not LPA-mediated production of NO. Using phospho-specific antibodies, we observed that either adiponectin or insulin treatment (but not LPA treatment) caused phosphorylation of both Akt at Ser473 and endothelial nitric-oxide synthase (eNOS) at Ser1179 that was inhibitable by wortmannin. We next transfected bovine aortic endothelial cells with dominant-inhibitory mutants of Akt (Akt-AAA) or AMP-activated protein kinase (AMPK) (AMPKK45R). Neither mutant affected production of NO in response to LPA treatment. Importantly, only AMPKK45R, but not Akt-AAA, caused a significant partial inhibition of NO production in response to adiponectin. Moreover, AMPK-K45R inhibited phosphorylation of eNOS at Ser1179 in response to adiponectin but not in response to insulin. We conclude that adiponectin has novel vascular actions to directly stimulate production of NO in endothelial cells using phosphatidylinositol 3-kinase-dependent pathways involving phosphorylation of eNOS at Ser1179 by AMPK. Thus, the effects of adiponectin to augment metabolic actions of insulin in vivo may be due, in part, to vasodilator actions of adiponectin.

AMP-Activated Protein Kinases↗