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PubMed2005

Adiponectin activates c-Jun NH2-terminal kinase and inhibits signal transducer and activator of transcription 3.

Adiponectin, a major adipose cytokine, plays a crucial role in the inhibition of metabolic syndrome by acting on such cell types as muscle cells and hepatocytes. Furthermore, evidence suggests that adiponectin may influence cancer pathogenesis. Adiponectin occurs in non-proteolytic (full-length adiponectin: f-adiponectin) and proteolytic (globular adiponectin: g-adiponectin) forms in various oligomeric states. Different forms of adiponectin show distinct biological effects through differential activation of downstream signaling pathways. Here we identify c-Jun NH(2)-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT3) as common downstream effectors of f- and g-adiponectin. f- and g-adiponectin both stimulate JNK activation in prostate cancer DU145, PC-3, and LNCaP-FGC cells, hepatocellular carcinoma HepG2 cells, and C2C12 myoblasts. Furthermore, both f- and g-adiponectin drastically suppress constitutive STAT3 activation in DU145 and HepG2 cells. These suggest that JNK and STAT3 may constitute a universal signaling pathway to mediate adiponectin's pathophysiological effects on metabolic syndrome and cancer.

Adiponectin↗
PubMed2006

Adiponectin and glucose levels in women with negative or false positive glucose challenge test.

OBJECTIVE: To determine whether there is a correlation between adiponectin levels and glucose levels in women screened for gestational diabetes mellitus by means of a 50-g oral glucose challenge test, and to examine the difference in adiponectin levels between women who tested negative, and those who tested false positive. We further calculated the correlations between adiponectin levels and glucose levels, body mass index, gestational age and maternal age. METHODS: A case control study included 171 mothers with negative or false positive results in the 1-h 50-g glucose challenge test at 24-28 gestational weeks. Serum adiponectin levels were determined by radioimmunoassay at the time of the glucose challenge test. RESULTS: There was a significant difference between women who tested negative at screening, and those who tested false positive with respect to age, prepregnancy body weight and body mass index, and adiponectin levels. Correlation analysis showed adiponectin levels to be negatively correlated to glucose levels (r=-0.193, P=0.011). To examine the association between glucose levels, adiponectin levels and demographic variables, multiple linear regression analysis was carried out. Prepregnancy body mass index and age accounted for 14.6% of the variance in the glucose challenge test. Adiponectin levels did not contribute independently to the variation in glucose levels. A further multiple linear regression analysis was undertaken to investigate the association between adiponectin levels and age, prepregnancy body mass index and glucose levels in the glucose challenge test. In this regression model, prepregnancy body mass index and age explained 12.1% of the variance in adiponectin levels. CONCLUSIONS: In conclusion, our study indicated a negative correlation between adiponectin and glucose levels in women screened for gestational diabetes mellitus by a glucose challenge test. We further found that maternal age and body mass index were independent risk factors for a false positive glucose challenge test. Reduced adiponectin levels in women who tested false positive on the glucose challenge test were dependent on advanced age and higher body mass index.

Adiponectin↗
PubMed2006

Plasma adiponectin levels are associated with coronary lesion complexity in men with coronary artery disease.

OBJECTIVES: We sought to assess whether plasma adiponectin levels correlate with angiographic coronary lesion complexity in patients with coronary artery disease (CAD). BACKGROUND: Metabolic disorders, including diabetes mellitus and metabolic syndrome, are important risk factors for acute cardiovascular events, and adiponectin is a key molecule of metabolic disorders, with anti-atherogenic properties. Low plasma adiponectin levels are associated with CAD and future incidence of myocardial infarction. The involvement of adiponectin in coronary plaque vulnerability, which may be reflected by angiographic complex lesions, remains to be elucidated. METHODS: We measured plasma adiponectin levels in 207 men (152 with stable CAD and 55 with acute coronary syndromes [ACS]). Coronary lesions were classified as of simple or complex appearance. RESULTS: Plasma adiponectin levels were significantly lower in stable CAD patients with complex coronary lesions (n = 60) than in those with simple lesions (n = 92) (4.14 [range 2.95 to 6.02] vs. 5.27 [range 3.67 to 8.12] microg/ml, p = 0.006). Multiple logistic regression analysis demonstrated that adiponectin level was independently associated with complex lesions (odds ratio 0.514, 95% confidence interval 0.278 to 0.951; p = 0.034). Polytomous logistic regression revealed that adiponectin correlated independently with both single and multiple complex lesions. Among patients with ACS, who had lower adiponectin levels than stable CAD patients, those with multiple complex lesions had significantly lower adiponectin than those with a single complex lesion (3.26 [range 2.26 to 4.46] vs. 4.21 [range 3.36 to 5.41] microg/ml, p = 0.032). CONCLUSIONS: Plasma adiponectin levels are significantly associated with coronary lesion complexity in men with CAD. Low adiponectin levels may contribute to coronary plaque vulnerability.

Acute Disease↗
PubMed2005

Adolescent sex differences in adiponectin are conditional on pubertal development and adiposity.

OBJECTIVE: Adiponectin is an adipose tissue protein with important insulin-sensitizing, anti-inflammatory, and cardioprotective properties but is paradoxically lower in obese individuals. Sex differences in adiponectin have been reported in adults and adolescents but not in prepubertal children. In this study, we hypothesized that sex differences in adiponectin would develop during puberty and would be influenced by level of adiposity. RESEARCH METHODS AND PROCEDURES: Adiponectin levels were measured in 1196 white and African-American adolescents. Insulin resistance was estimated using the homeostasis model (HOMA-IR). Demographic, developmental, and metabolic variables, including interactions with adiposity measurements, were evaluated for independent relationships with adiponectin levels. RESULTS: Overall, adiponectin levels varied significantly by sex, race, adiposity, and puberty stage. Significant sex differences in adiponectin developed after the onset of puberty, particularly in lean adolescents. Adolescent boys had lower adiponectin levels in post-puberty compared with pre-puberty (p = 0.01) and had lower levels than girls in both puberty and post-puberty (both p < 0.001), after adjusting for race, BMI z-score, and natural logarithm-(HOMA-IR). Sex differences were also conditional on adiposity level, with significant sex differences among lean (p < 0.001) but not among non-lean (p = 0.16) adolescents. Adiponectin levels in girls decreased more with increasing adiposity than in boys (p = 0.004), but only marginally so after standardizing for girls' higher mean adiponectin level (p = 0.11). DISCUSSION: Sex differences in adiponectin are dependent on both puberty stage and adiposity in adolescents, such that by post-puberty, non-lean boys exhibit the lowest levels of adiponectin.

Adiponectin↗
PubMed2000

Genomic structure and mutations in adipose-specific gene, adiponectin.

BACKGROUND: Adiponectin is a collagen-like plasma protein specifically synthesized in adipose tissue. Plasma adiponectin concentrations are decreased in obesity whereas it is adipose-specific. OBJECTIVE: To clarify the significance of the genetic variations in adiponectin gene on its plasma concentrations and obesity. SUBJECTS: Two hundred and nineteen unrelated adult Japanese subjects (123 men and 96 women, age: 20-83 y, BMI: 16-43 kg/m2) including 77 obese subjects (BMI>26.4 kg/m2). MEASUREMENT: Human adiponectin gene was isolated from PAC DNA pools. Mutations in the adiponectin gene were screened by direct sequencing or restriction-fragment polymorphism. The levels of plasma adiponectin were determined by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Adiponectin gene spanned 17 kb on chromosome 3q27, consisting of three exons and two introns. Within 2.1 kb of the 5'-flanking region, there were two octamer elements present in the promoter of adipsin. Two nucleotide changes were identified. One was a polymorphism (G/T) occurring in exon 2, and the other was a missense mutation (R112C) in exon 3. The mean plasma adiponectin levels of the subjects carrying G allele were low (G/G: 4.5 microg/ml; G/T: 5.9 microg/ml; and T/T: 6.3 microg/ml), but were not statistically significant. The allelic frequency between the obese and the non-obese showed no significant difference. The subject carrying R112C mutation showed markedly low concentration of plasma adiponectin. CONCLUSION: Two nucleotide changes have been identified in the adiponectin gene. G/T polymorphism in exon 2 was associated with neither plasma adiponectin concentrations nor the presence of obesity. A subject carrying missense mutation (R112C) showed markedly low plasma adiponectin concentration.

Adipocytes↗
PubMed2006

Adiponectin, insulin resistance and clinical expression of the metabolic syndrome in patients with Type 2 diabetes.

BACKGROUND: Obesity and the metabolic syndrome have emerged as clinical and public health crises in many populations, but not all obese patients have the syndrome. As adipocytes produce several adipokines that modulate insulin action as well as glucose and lipid metabolism, we postulate that estimation of adipokines may be useful addition to the criteria used to identify obese individuals with the metabolic syndrome. OBJECTIVE: To evaluate the determinants and associations of plasma adiponectin in relation to the metabolic syndrome in patients with Type 2 diabetes. DESIGN: Cross-sectional study. SETTING: General Teaching Hospital. PATIENTS: One hundred and thirty five (57 M, 78 F) patients with Type 2 diabetes mellitus. MEASUREMENTS: Adiponectin, leptin, high-sensitivity C-reactive protein (hs-CRP), fasting plasma insulin, glucose, glycated hemoglobin and full lipid profile. Patients were classified on the basis of the degree of adiposity, insulin resistance (IR) (homeostasis model assessment of insulin resistance (HOMA-IR)) and the number of the American Heart Association and the National Heart, Lung and Blood Institute criteria of the metabolic syndrome. RESULTS: Adiponectin levels were inversely correlated with age, indices of obesity, IR and hs-CRP. Overweight/obese and non-obese insulin-sensitive patients had significantly higher (P<0.05) adiponectin levels than those with IR despite similar body mass index and waist circumference. Therefore, within each category of obesity stratification, lower adiponectin levels were associated with IR. Adiponectin showed stepwise decrease with increasing number of the criteria for diagnosis of the metabolic syndrome. Using multiple logistic regression, the odds ratio of the metabolic syndrome as predicted by adiponectin was 0.73 (95% confidence interval 0.53-0.96; P=0.04). At cutoff point of 18 ng/ml, the diagnostic sensitivity and specificity of adiponectin for the metabolic syndrome were 83 and 65%, respectively, in male patients and 92 and 41%, respectively, in female patients. Receiver operating characteristic analysis showed that adiponectin had significantly higher area under the curve compared with leptin, leptin:adiponectin ratio and triglycerides for the detection of the metabolic syndrome. CONCLUSIONS: In patients with Type 2 diabetes, adiponectin concentrations are closely related to IR and the components of the metabolic syndrome. Adiponectin concentration may be a useful addition to the criteria used for identifying obese subjects with the metabolic syndrome.

Adiponectin↗
PubMed2003

Fasting serum adiponectin concentration is reduced in Indo-Asian subjects and is related to HDL cholesterol.

AIMS: Adiponectin is a 30-kDa protein secreted by adipose tissue. The aim of the present study was to compare serum adiponectin in male Indo-Asian and Caucasian subjects and examine its association with fat topography and metabolic parameters. METHODS: Diabetic and non-diabetic male subjects (n = 48) were studied. A single observer carried out blood pressure and anthropometric measurements. Serum glucose, insulin, lipid profile and adiponectin (measured by RIA) were measured on a fasting sample. RESULTS: There was no statistically significant difference in serum adiponectin between diabetic and BMI-matched non-diabetic subjects. However, serum adiponectin was lower in Indo-Asians compared with BMI-matched Caucasians, [median adiponectin (interquartile range) 3.3 (2.1-3.9) vs. 4.9 (3.5-6.6) microg/ml respectively (p = 0.016)]. Univariate analysis showed serum adiponectin to be positively associated with HDL in diabetic (p = 0.039) and non-diabetic subjects (p = 0.0098). Waist circumference (p = 0.02), saggital diameter (p = 0.04) were negatively correlated with serum adiponectin in diabetic subjects. Multiple regression analysis including waist, HDL, fasting insulin, age, diabetes and ethnicity in all subjects showed HDL to be the best predictor of serum adiponectin. CONCLUSIONS: Serum adiponectin is associated with HDL cholesterol and central obesity. Caucasians have higher serum adiponectin levels compared with Indo-Asians. Further studies are needed to explore basis for the association of adiponectin with HDL cholesterol and the reason for lower levels in Indo-Asians.

Adiponectin↗
PubMed2003

Plasma adiponectin in overweight, nondiabetic individuals with or without insulin resistance.

AIM: Adiponectin is a protein produced exclusively by adipocytes with putative insulin-sensitizing and anti-atherogenic properties. This cross-sectional study investigated the relationship between plasma adiponectin and a range of anthropometric, glycaemic, lipid and inflammatory parameters in overweight and obese subjects expressing characteristics of the metabolic syndrome. METHODS: Subjects were selected for the study from a clinical database, if they were non-diabetic, overweight [body mass index (BMI) > 25] and had features of the metabolic syndrome. The subjects were grouped according to BMI (25-30, 31-35 and >35 kg/m2) and then stratified for insulin resistance [homeostasis model assessment (HOMA) %S]. One hundred and ninety-seven patients (109 males and 88 females) were selected for the study by taking an equal number with the highest and lowest HOMA indices from each of the three BMI groups. Plasma adiponectin concentration was measured in duplicate by radioimmunoassay, and the relationship between these levels and the other parameters was investigated using correlation and multiple linear regression analyses. RESULTS: Plasma adiponectin concentration was higher in females than males (median 10.3 vs. 7.1 micro g/ml, p < 0.001) despite being matched for BMI. In both genders, adiponectin levels were inversely related to BMI, waist circumference, percentage body fat, insulin resistance and the fasting plasma concentration of leptin. A direct correlation in both sexes was found between adiponectin levels and high-density lipoprotein (HDL)-cholesterol, apolipoprotein A1 and age. Multiple linear regression analyses showed that the independent determinants of low plasma adiponectin concentrations were gender, age, BMI, insulin resistance and HDL-cholesterol. An association between reduced adiponectin and increased high-sensitivity plasma C-reactive protein concentration was observed only in female subjects and was independent of anthropometric variables. Our observation that adiponectin levels increase with age differs from the majority of other studies and may simply reflect the demographics of the population studied. CONCLUSIONS: This study shows that adiponectin is an important molecular link between obesity, insulin resistance and atherogenic lipoproteins. It is possible that plasma adiponectin concentration may be a convenient marker for identifying subjects with the metabolic syndrome who may progress to impaired glucose tolerance. Longitudinal studies are required in order to verify this clinical application of adiponectin.

Adiponectin↗
PubMedDate not supplied

Differences in adiponectin protein expression: effect of fat depots and type 2 diabetic status.

Adiponectin is an adipocyte-derived hormone associated with insulin sensitivity and atherosclerotic risk. As central rather than gluteofemoral fat is known to increase the risk of type 2 diabetes and cardiovascular disease, we investigated the mRNA and protein expression of adiponectin in human adipose tissue depots. RNA was extracted from 46 human adipose tissue samples from non-diabetic subjects aged 44.33 +/- 12.4 with a BMI of 28.3 +/- 6.0 (mean +/- SD). The samples were as follows: 21 abdominal subcutaneous, 13 omentum, 6 thigh; samples were also taken from diabetic subjects aged 66.6 +/- 7.5 with BMI 28.9 +/- 3.17; samples were: 6 abdominal subcutaneous; 3 thigh. Quantitative PCR and Western analysis was used to determine adiponectin content. Protein content studies determined that when compared with non-diabetic abdominal subcutaneous adipose tissue (Abd Sc AT) (values expressed as percentage relative to Abd Sc AT -100 %). Adiponectin protein content was significantly lower in non-diabetic omental AT (25 +/- 1.6 %; p < 0.0001, n = 6) and in Abd Sc AT from diabetic subjects (36 +/- 1.5 %; p < 0.0001, n = 4). In contrast, gluteal fat maintained high adiponectin protein content from non-diabetic patients compared with diabetic patients. An increase in BMI was associated with lower adiponectin protein content in obese ND Abd Sc AT (25 +/- 0.4 %; p < 0.0001). These findings were in agreement with the mRNA expression data. In summary, this study indicates that adiponectin protein content in non-diabetic subjects remains high in abdominal subcutaneous fat, including gluteal fat, explaining the high serum adiponectin levels in these subjects. Omental fat, however, expresses little adiponectin. Furthermore, abdominal and gluteal subcutaneous fat appears to express significantly less adiponectin once diabetic status is reached. In conclusion, the adipose tissue depot-specific expression of adiponectin may influence the pattern of serum adiponectin concentrations and subsequent disease risk.

Adipocytes↗
PubMed2005

Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner.

Adiponectin, an adipocyte-specific secretory protein, is present in serum as three oligomeric complexes. Apart from its roles as an anti-diabetic and anti-atherogenic hormone, adiponectin has been implicated as an important regulator of cell growth and tissue remodeling. Here we show that some of these functions might be mediated by the specific interactions of adiponectin with several important growth factors. Among six different growth factors examined, adiponectin was found to bind with platelet-derived growth factor BB (PDGF-BB), basic fibroblast growth factor (FGF), and heparin-binding epidermal growth factor-like growth factor (HB EGF) with distinct affinities. The bindings of adiponectin with these growth factors are oligomerization-dependent. PDGF-BB bound to the high molecular weight (HMW) and middle molecular weight (MMW) complexes, but not to the low molecular weight (LMW) complex of adiponectin. Basic FGF preferentially interacted with the HMW form, whereas HB EGF bound to all three forms with comparable affinities. These three growth factors did not compete with each other for their bindings to adiponectin, suggesting the involvement of distinct binding sites. The interactions of adiponectin with PDGF-BB, basic FGF, and HB EGF precluded the bindings to their respective membrane receptors and attenuated the DNA synthesis and cell proliferation induced by these growth factors. Small interfering RNA-mediated down-regulation of adiponectin receptors did not affect the suppressive effects of adiponectin on cell proliferation stimulated by these growth factors. These data collectively suggest that the oligomeric complexes of adiponectin can modulate the biological actions of several growth factors by controlling their bioavailability at a pre-receptor level and that this effect might partly account for the anti-atherogenic, anti-angiogenic, and anti-proliferative functions of adiponectin.

Adiponectin↗
PubMed2005

Plasma adiponectin is modestly decreased during 24-hour insulin infusion but not after inhibition of lipolysis by Acipimox.

OBJECTIVE: Plasma adiponectin is associated with insulin resistance and atherosclerosis. Adiponectin expression in adipose tissue is up-regulated by peroxisome proliferator-activated receptor (PPAR)-gamma agonist treatment and its plasma level may be affected by insulin. We tested the hypothesis that prolonged exogenous insulin infusion decreases plasma adiponectin, and examined whether a possible effect of insulin on plasma adiponectin is attributable to inhibition of lipolysis. MATERIAL AND METHODS: The effect of insulin infusion on plasma adiponectin (Linco enzyme-linked immunosorbent assay) was evaluated during a 24-h moderately hyperinsulinemic clamp (8.3 microU kg(-1) s(-1)) in 8 male type 2 diabetic patients and in 8 healthy men. On a separate day, acipimox (250 mg/4 h for 24 h) was administered to inhibit lipolysis. Insulin and acipimox were administered in random order with 1 week between study days. RESULTS: In type 2 diabetic patients, insulin infusion decreased plasma adiponectin from 7.74+/-2.53 mg/l to 6.76+/-2.41 mg/l after 24 h (p<0.05). In healthy subjects, the change in plasma adiponectin after 24 h of insulin was not significant (8.10+/-2.76 and 7.55+/-2.41 mg/l at baseline and after 24 h of insulin, respectively). The change in plasma adiponectin after 24 h insulin in healthy subjects was not different from the change in diabetic patients. Plasma adiponectin did not decrease after 24 h acipimox administration in either group (type 2 diabetic patients: 6.84+/-2.19 and 6.54+/-2.93 mg/l at baseline and after 24 h, respectively (NS); healthy subjects; 7.35+/-2.52 and 8.31+/-3.37 mg/l, at baseline and after 24 h, respectively (NS)). When the results from diabetic and healthy subjects were combined, the decrease in plasma adiponectin after 24 h of insulin infusion (-0.76+/-1.08 mg/l, equivalent to a -9% change from baseline, p<0.05) was different (p = 0.05) from the change after 24 h acipimox (+0.33+/-1.74 mg/l, equivalent to a +4% change from baseline). Plasma free fatty acids decreased during insulin infusion (p<0.01 for both groups after 24 h) as well as in response to acipimox (p<0.05 for healthy subjects; p<0.01 type 2 diabetic patients after 24 h). After administration of acipimox, plasma insulin did not change in either group. CONCLUSIONS: Plasma adiponectin is modestly decreased during 24 h of insulin infusion. It is unlikely that this response to exogenous insulin is attributable to inhibition of lipolysis, since plasma adiponectin did not decrease after acipimox.

Adiponectin↗
PubMed2006

Adiponectin is present in human milk and is associated with maternal factors.

BACKGROUND: Previous studies have shown that human milk has a role in the gastrointestinal, neural, and immune development of neonates. If present in milk, adiponectin would be a promising candidate for influencing infant development, given its metabolic functions. OBJECTIVES: Our objectives were to determine whether adiponectin is present in human milk and to characterize maternal factors associated with potential variation in milk adiponectin concentrations. DESIGN: We quantified adiponectin concentrations in human milk samples from donors to the Cincinnati Children's Research Human Milk Bank and randomly selected participants in a cohort study in Mexico City funded by the National Institutes of Health. Using cross-sectional and longitudinal data, we examined milk adiponectin concentrations in relation to lactation duration, maternal body mass index (BMI; in kg/m(2)), and ethnicity. RESULTS: Adiponectin was detected in human skim milk (range: 4.2-87.9 ng/mL). In cross-sectional and longitudinal analyses, duration of lactation was negatively associated with milk adiponectin concentrations (beta = -0.059 +/- 0.024 and -0.059 +/- 0.007, respectively; P < 0.02 for both). Maternal postpregnancy BMI was positively associated with milk adiponectin concentrations (beta = 0.08 +/- 0.02, P < 0.0001; longitudinal analysis). Mexican mothers had lower median milk adiponectin concentrations at 1 mo than did the non-Hispanic white subjects from Cincinnati (11.5 and 19.8 ng/mL; P = 0.003). CONCLUSIONS: Adiponectin is present in human milk and its concentrations are associated with duration of lactation, maternal adiposity, and ethnicity. Given the importance of adiponectin in inflammation, insulin sensitivity, and fatty acid metabolism, future studies should examine milk adiponectin's role in infant metabolic development.

Adiponectin↗
PubMed2004

Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy.

OBJECTIVE: Adiponectin is an adipocyte-specific secretory protein which exhibits antiatherogenic, anti-inflammatory and antidiabetic properties. We hypothesized that testosterone plays an important role in the regulation of its secretion in humans, as adiponectin concentrations are higher in women than in men and as testosterone administration is accompanied by a reduction in serum adiponectin in animals and by reduced protein secretion in cultured adipocytes. This study aimed to evaluate adiponectin levels in hypogonadal men prior to and during testosterone replacement therapy. SUBJECTS AND METHODS: In a retrospective study, adiponectin, total and free testosterone, oestradiol, SHBG, total cholesterol and triglyceride levels were evaluated in 31 hypogonadal men [HM; age, mean +/- SEM: 36.5 +/- 2.4 years; body mass index (BMI) 24.6 +/- 0.8 kg/m2] and 29 weight-matched eugonadal men (EM; age 30.8 +/- 1.5 years; BMI 23.4 +/- 0.6 kg/m2). In 13 HM (age 33.9 +/- 3.2 years; BMI 24.2 +/- 0.9 kg/m2) the same parameters were also evaluated after 6 months of testosterone replacement therapy. Correlation analysis between adiponectin and hormonal, biochemical and anthropometric parameters was performed in all subjects. RESULTS: Testosterone, free testosterone and oestradiol concentrations were significantly lower in HM than in EM (4.4 +/- 0.4 nmol/l, 78.4 +/- 10.9 pmol/l and 36.1 +/- 3.0 pmol/l, respectively, in HM vs. 21.9 +/- 0.7 nmol/l, 507.9 +/- 13.8 pmol/l and 65.2 +/- 1.8 pmol/l, respectively, in EM, P < 0.0001), while SHBG levels in HM were higher than in EM (54.4 +/- 7.5 vs. 30.9 +/- 2.2 nmol/l, P < 0.005). Serum adiponectin levels in HM were significantly higher than in EM (9.53 +/- 0.73 vs. 6.80 +/- 0.55 microg/ml, P < 0.01). Calculation of the Pearson coefficient showed that adiponectin levels in HM were not correlated with any of the anthropometric and hormonal parameters examined, but showed a significant negative correlation with serum triglycerides (r = -0.38, P < 0.05). Serum adiponectin levels were negatively correlated with body weight (r = -0.41, P < 0.05) in EM but not with other anthropometric, hormonal or biochemical parameters. Six months after initiation of testosterone replacement therapy, which increased testosterone and free testosterone levels to the normal range, adiponectin levels were significantly reduced in HM (6.37 +/- 0.93 vs. 9.26 +/- 1.01 microg/ml, P < 0.01) and similar to those recorded in EM. CONCLUSIONS: Compared to eugonadal subjects, hypogonadal men show higher adiponectin levels which are reduced by testosterone replacement therapy. This study indicates that testosterone exerts a regulatory role on adiponectin secretion in humans.

Adiponectin↗
PubMed2005

Adiponectin: action, regulation and association to insulin sensitivity.

Adiponectin is a novel adipocyte-specific protein, which, it has been suggested, plays a role in the development of insulin resistance and atherosclerosis. Although it circulates in high concentrations, adiponectin levels are lower in obese subjects than in lean subjects. Apart from negative correlations with measures of adiposity, adiponectin levels are also reduced in association with insulin resistance and type 2 diabetes. Visceral adiposity has been shown to be an independent negative predictor of adiponectin. Thus, most features of the metabolic syndrome's negative associations with adiponectin have been shown. Adiponectin levels seem to be reduced prior to the development of type 2 diabetes, and administration of adiponectin has been accompanied by lower plasma glucose levels as well as increased insulin sensitivity. Furthermore, reduced expression of adiponectin has been associated with some degree of insulin resistance in animal studies indicating a role for hypoadiponectinaemia in relation to insulin resistance. The primary mechanisms by which adiponectin enhance insulin sensitivity appears to be through increased fatty acid oxidation and inhibition of hepatic glucose production. Adiponectin levels are increased by thiazoledinedione treatment, and this effect might be important for the enhanced insulin sensitivity induced by thiazolidinediones. In contrast, adiponectin levels are reduced by pro-inflammatory cytokines especially tumour necrosis factor-alpha. In summary, adiponectin in addition to possible anti-inflammatory and anti-atherogenic effects appears to be an insulin enhancer, with potential as a new pharmacologic treatment modality of the metabolic syndrome and type 2 diabetes.

Adiponectin↗
PubMed2003

Increased expression of TNF-alpha, IL-6, and IL-8 in HALS: implications for reduced adiponectin expression and plasma levels.

Human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) is a side effect of highly active antiretroviral therapy of HIV-infected patients; however, the mechanism of the lipodystrophy and insulin resistance seen in this syndrome remains elusive. Adiponectin, an adipocyte-specific protein, is thought to play an important role in regulating insulin sensitivity. We investigated circulating levels and gene expression of adiponectin in subcutaneous abdominal adipose tissue (AT) from 18 HIV-infected patients with HALS compared with 18 HIV-infected patients without HALS. Implications of cytokines for adiponectin levels were investigated by determining circulating levels of TNF-alpha, IL-6, and IL-8 as well as gene expression of these cytokines in AT. HALS patients exhibited 40% reduced plasma adiponectin levels (P < 0.05) compared with non-HALS subjects. Correspondingly, adiponectin mRNA levels in AT were reduced by >50% (P = 0.06). HALS patients were insulin resistant, and a positive correlation was found between plasma adiponectin and insulin sensitivity (r = 0.55, P < 0.01) and percent limb fat (r = 0.61, P < 0.01). AT mRNA of TNF-alpha, IL-6, and IL-8 was increased in AT of HALS subjects (P < 0.05), and both AT TNF-alpha mRNA and plasma TNF-alpha were negatively correlated to plasma adiponectin (P < 0.05). Finally, TNF-alpha was found in vitro to inhibit human AT adiponectin mRNA by 80% (P < 0.05). In conclusion, HALS patients have reduced levels of plasma adiponectin and adiponectin mRNA in AT. Increased cytokine mRNA in AT is hypothesized to exert an inhibitory effect on adiponectin gene expression and, consequently, to play a role in the reduced plasma adiponectin levels found in HALS patients.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Increased plasma adiponectin in response to pioglitazone does not result from increased gene expression.

Plasma levels of adiponectin are lower in obese and insulin-resistant subjects compared with lean and insulin-sensitive ones. Thiazolidinediones increase plasma adiponectin levels in diabetic subjects, although the mechanism of this increased plasma adiponectin has not been well studied. In the present study, we compared the plasma levels and adipose tissue expression of adiponectin in subjects with normal (NGT) and impaired glucose tolerance (IGT) and also studied the effects of metformin and pioglitazone on plasma and adipose tissue mRNA level of adiponectin in IGT subjects. IGT subjects had lower plasma adiponectin levels compared with NGT subjects, and similarly IGT subjects had lower adiponectin mRNA levels. In contrast, the increased plasma levels of adiponectin in response to pioglitazone were not associated with increased adiponectin expression in adipose tissue. Metformin did not cause any change in plasma or expression levels of adiponectin. Other adipokines were examined, and both pioglitazone and metformin decreased plasma levels of resistin in IGT subjects, and pioglitazone (but not metformin) decreased plasma levels of leptin. These data suggest that pioglitazone increases plasma adiponectin levels by posttranscriptional regulation in contrast to transcriptional regulation of adiponectin in relation to insulin sensitivity in NGT vs. IGT subjects.

Abdominal Fat↗
PubMed2006

Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level.

OBJECTIVE: Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells. METHODS AND RESULTS: Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPARalpha-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi. CONCLUSIONS: Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

Adipocytes↗
PubMed2000

Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway.

BACKGROUND: Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-alpha (TNF-alpha)-induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (CIRCULATION: 1999;100:2473-2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin. METHODS AND RESULTS: The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 microg/mL of adiponectin, then exposed to TNF-alpha (10 U/mL) or vehicle for the times indicated. NF-kappaB-DNA binding activity was determined by electrophoretic mobility shift assays. TNF-alpha-inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-alpha-induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF-alpha and its receptors. Adiponectin suppressed TNF-alpha-induced IkappaB-alpha phosphorylation and subsequent NF-kappaB activation without affecting other TNF-alpha-mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blocked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor. CONCLUSIONS: These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-kappaB signaling pathways.

Adenylyl Cyclase Inhibitors↗