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PubMed2004

Adiponectin before and after weight loss in obese children.

Adiponectin is decreased in obesity and seems to be involved in insulin resistance. The influences of age, gender, puberty, and weight loss on adiponectin have not been studied in obese children. We measured body fat mass based on skinfold thickness, age, pubertal stage, gender, adiponectin, and insulin resistance (homeostasis model assessment) in 42 obese children. We analyzed adiponectin and homeostasis model assessment 1 yr later in these obese children and separated them into two groups according to degree of weight loss (decrease in sd score for body mass index, >or=0.5 vs. <0.5). Adiponectin was negatively correlated to percentage body fat (r = -0.44; P = 0.002), insulin resistance (r = -0.33; P = 0.016), and age (r = -0.41; P = 0.003). Adiponectin levels were significantly (P = 0.017) higher in pubertal girls compared with boys, but there was no significant difference in prepubertal children in respect to gender (P = 0.833). Adiponectin was significantly (P < 0.001) lower in pubertal compared with prepubertal children. The significant weight loss in 16 children was associated with a significant increase in adiponectin (P = 0.010) and a decrease in insulin resistance (P = 0.013), whereas there were no changes in the 26 children without significant weight loss. Adiponectin levels in obese children were negatively correlated to age, body fat, and insulin resistance and were decreased in puberty. Significant weight loss led to an increase in adiponectin levels and an improvement of insulin resistance.

Adiponectin↗
PubMed2004

Cord plasma adiponectin: a 20-fold rise between 24 weeks gestation and term.

Adiponectin is an adipocyte-derived hormone with profound insulin-sensitizing, antiinflammatory, and antiatherogenic effects. Apart from its obvious potential as a mediator of adult metabolic syndrome, adiponectin could have a significant role in regulating fetal growth.We measured plasma adiponectin concentrations by ELISA in cord vein of 197 infants. Of them, 122 were born preterm (gestational age, 22-32 wk), and 75 at term (49 from a healthy and 26 from a diabetic pregnancy, with similar findings, and thus all data from term infants pooled).Mean adiponectin concentrations increased from less than 1 microg/ml at 24 wk gestation to approximately 20 microg/ml at term. One week increase in gestational age corresponded in preterm infants to 43% increase (95% confidence interval 34-53%; P < 0.0001) in adiponectin and term infants to 21% increase (12-31%; P < 0.0001). In preterm infants, one unit increase in birth weight sd score corresponded to 42% increase (22-66%; P = 0.0001) in adiponectin, and females had 57% higher adiponectin concentrations (0-146%; P = 0.05) than males. These differences were not seen in term infants. Adiponectin levels were lower in preterm infants with recent (<12 h) exposure to maternal betamethasone but were unrelated to mode of delivery, preeclampsia, or impaired umbilical artery flow. In conclusion, adiponectin concentrations in fetal circulation show a 20-fold rise between 24 wk gestation and term and, in preterm infants are associated with birth weight sd score, sex, and glucocorticoid exposure. Adiponectin may play an important role in regulating fetal growth and explaining its links to the metabolic syndrome and its consequences during adult life.

Adiponectin↗
PubMed2004

Adiponectin levels in the first two years of life in a prospective cohort: relations with weight gain, leptin levels and insulin sensitivity.

Adiponectin, a novel adipocytokine with insulin sensitizing properties, is inversely related to obesity and insulin resistance in adults. We recently reported large variations in weight gain and insulin sensitivity during the first year in infants born small for gestational age (SGA) or appropriate for gestational age (AGA). We now determined whether adiponectin levels were related to postnatal growth and insulin sensitivity in a prospective cohort followed from birth to two years old (n = 85) (55 female/30 male, 65 SGA/20 AGA). Serum adiponectin levels at one year and two years were higher compared to reported levels in adults and older children, and decreased from one year (21.6 +/- 0.6 microg/ml) to two years (15.7 +/- 0.7 microg/ml) (p < 0.05). At two years adiponectin levels were lower in females (15.3 +/- 0.4 microg/ml) than males (16.4 +/- 0.6 microg/ml) (p < 0.05), but no gender difference was seen in leptin or insulin levels. No differences in adiponectin levels were seen between SGA and AGA infants at one or two years. However, in SGA infants changes in adiponectin between one to two years old were inversely related to weight gain (r = -0.310, p < 0.05). Changes in leptin levels between one to two years were positively related to weight gain in both SGA and AGA infants (r = 0.450 and r = 0.500 respectively, both p < 0.05). Adiponectin levels were unrelated to insulin levels at one or two years, nor to change in insulin levels between one to two years. In multiple regression analysis, adiponectin levels were related only to postnatal age; omitting age from the model, the determinants of higher adiponectin levels were male gender (p = 0.03), lower postnatal body weight (p < 0.001), and higher birth weight SD score (p = 0.004). In conclusion, fall in serum adiponectin levels during the first two years of life were related to increasing age and greater weight gain SGA infants, but were unrelated to insulin sensitivity.

Adiponectin↗
PubMed2005

Mature subcutaneous and visceral adipocyte concentrations of adiponectin are highly correlated in prepubertal children and inversely related to body mass index standard deviation score.

CONTEXT: Adiponectin is an adipocyte-specific protein with insulin-sensitizing properties. Several studies have examined the expression of adiponectin mRNA or tissue/secreted protein levels in fat obtained from adults, but none has assessed tissue levels in childhood. PATIENTS: Paired subcutaneous (Sc) and visceral (V) fat samples were obtained from 12 normal-weight children. MAIN OUTCOME MEASURES: Mature adipocytes were isolated and total adiponectin levels determined by ELISA. Insulin sensitivity and lipid parameters were assessed in fasting blood samples taken at the time of biopsy collection. RESULTS: A positive correlation was seen between the adiponectin concentration within the Sc and V mature adipocytes derived from each child (r = 0.924; P < 0.001). After logarithmic transformation of the Sc and V adiponectin concentrations (log-Sc and log-V) to render the data Gaussian, both log-Sc and log-V were found to be lower in those children with higher body mass index sd score (r = -0.621 and r = -0.357 respectively), although this reached statistical significance only in the Sc adipocytes (P = 0.03). Age was not related to either log-Sc or log-V adiponectin levels, although a significant negative association was seen with serum adiponectin (r = -0.589; P = 0.04). Log-Sc or log-V did not correlate with serum adiponectin concentrations, markers of insulin sensitivity, or circulating lipid levels. CONCLUSIONS: These data indicate a relationship between total adiponectin levels in different tissue compartments, suggesting either some form of interaction or coregulation by systemic factors, possibly related to body size/fat mass. Serum concentrations of total adiponectin were inversely related to age but showed no relationship with either tissue levels or body mass index sd score.

Adipocytes↗
PubMed2006

The relationship between plasma adiponectin concentration and insulin resistance is altered in smokers.

CONTEXT: Low plasma adiponectin concentrations in smokers may contribute to the adverse consequences that occur in these individuals. OBJECTIVE: The objective of the study was to define the relationship among smoking, plasma adiponectin concentrations, insulin resistance, and inflammation. DESIGN: This was a cross-sectional, observational study with a 2 x 2 factorial design and a prospective longitudinal arm. SETTING: The study was conducted at a general clinical research center. PARTICIPANTS: Apparently healthy smokers (n = 30) and nonsmokers (n = 30), subdivided into insulin resistant (IR) (n = 15) and insulin sensitive (IS) (n = 15) subgroups participated in the study. INTERVENTION: Intervention included pioglitazone administration for 3 months to 12 IR smokers and eight IS smokers. MAIN OUTCOME MEASURES: Measures included fasting plasma adiponectin and C-reactive protein (CRP) concentrations and changes in adiponectin after pioglitazone treatment in IR and IS smokers. RESULTS: Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (P = 0.046 and 0.001, respectively). The difference in mean adiponectin concentration between smokers and nonsmokers did not depend on the insulin resistance status of the subjects. No difference was detected in average CRP concentrations between smokers and nonsmokers (P = 0.18) and between IR and IS subjects (P = 0.13). CRP concentrations were unrelated to adiponectin in smokers (r = -0.05, P = 0.78) and nonsmokers (r = 0.03, P = 0.86). Finally, pioglitazone treatment increased adiponectin concentrations in both IR (P < 0.001) and IS smokers (P = 0.001). CONCLUSIONS: Plasma adiponectin concentrations are lower in smokers and IR subjects and are unrelated to CRP concentrations. These findings suggest that low levels of adiponectin in smokers may be independent of both insulin resistance and a generalized inflammatory response.

Adiponectin↗
PubMed2006

Adiponectin multimerization is dependent on conserved lysines in the collagenous domain: evidence for regulation of multimerization by alterations in posttranslational modifications.

Adiponectin is a secreted, multimeric protein with insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Serum adiponectin consists of trimer, hexamer, and larger high-molecular-weight (HMW) multimers, and these HMW multimers appear to be the more bioactive forms. Multimer composition of adiponectin appears to be regulated; however, the molecular mechanisms involved are unknown. We hypothesize that regulation of adiponectin multimerization and secretion occurs via changes in posttranslational modifications (PTMs). Although a structural role for intertrimer disulfide bonds in the formation of hexamers and HMW multimers is established, the role of other PTMs is unknown. PTMs identified in murine and bovine adiponectin include hydroxylation of multiple conserved proline and lysine residues and glycosylation of hydroxylysines. By mass spectrometry, we confirmed the presence of these PTMs in human adiponectin and identified three additional hydroxylations on Pro71, Pro76, and Pro95. We also investigated the role of the five modified lysines in multimer formation and secretion of recombinant human adiponectin expressed in mammalian cell lines. Mutation of modified lysines in the collagenous domain prevented formation of HMW multimers, whereas a pharmacological inhibitor of prolyl- and lysyl-hydroxylases, 2,2'-dipyridyl, inhibited formation of hexamers and HMW multimers. Bacterially expressed human adiponectin displayed a complete lack of differentially modified isoforms and failed to form bona fide trimers and larger multimers. Finally, glucose-induced increases in HMW multimer production from human adipose explants correlated with changes in the two-dimensional electrophoresis profile of adiponectin isoforms. Collectively, these data suggest that adiponectin multimer composition is affected by changes in PTM in response to physiological factors.

2,2'-Dipyridyl↗
PubMed2006

Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease.

BACKGROUND: Adiponectin, an adipocyte-derived hormone, appears to be a modulator of lipid metabolism and systemic inflammation and is present in particularly low concentrations in patients with coronary heart disease (CHD). However, the clinical importance of adiponectin in individuals at markedly high risk for future cardiovascular morbidity and mortality has not been fully elucidated. We examined the associations between serum adiponectin and several biomarkers related to cardiovascular disease and heart failure in a large high-risk population comprising patients with prevalent CHD. METHODS: We measured fasting adiponectin, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and markers of lipoprotein metabolism in 1174 patients with CHD. RESULTS: After adjustment for age and sex, adiponectin was associated with HDL-cholesterol (HDL-C; r = 0.25; P <0.0001), NT-proBNP (r = 0.17; P <0.0001), and plasma triglyceride (r = -0.21; P <0.0001) concentrations. There was, however, no statistically significant association between adiponectin and markers of systemic inflammation. In partial correlation analyses further adjusted for body mass index, alcohol intake, smoking status, presence of diabetes and/or hypertension, lipid-lowering drug therapy, and fasting plasma glucose, adiponectin remained significantly associated with HDL-C (r = 0.21; P <0.0001), NT-proBNP (r = 0.15; P <0.0001), and plasma triglycerides (r = -0.16; P <0.0001). CONCLUSIONS: Serum adiponectin is associated with the presence of atherogenic dyslipidemia and with NT-proBNP concentration but not with markers of systemic inflammation in patients with manifest CHD. Thus, atherogenic dyslipidemia may link adiponectin with the progression of atherosclerosis. Moreover, serum adiponectin may be related to BNP in patients with CHD.

Adiponectin↗
PubMed2004

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist increases plasma adiponectin levels in type 2 diabetic patients with proteinuria.

Adiponectin appears to be an important modulator for metabolic and vascular diseases. A case-controlled study was designed to measure plasma adiponectin levels and investigate the effects of rosiglitazone on adiponectin levels in type 2 diabetic patients with proteinuria. Sixty-four patients (mean age, 46.1+/-4.6 yr; 30 male, 34 female) and 26 healthy volunteers (mean age, 45.3+/-4.8 yr; 14 male, 12 female) were included. Patients with proteinuria were treated with 4-mg/d rosiglitazone (n=21, 10 males, 11 females) for 4 wk. Adiponectin levels in patients were significantly lower than those of controls (p<0.001). There were significant negative correlations between adiponectin concentrations and insulin levels as well as homeostasis model assessment (HOMA) index in patient's group (r=- 0.538, p<0.001; r=- 0.393, p=0.001, respectively). There was also a significant negative correlation between plasma adiponectin concentrations and the degree of proteinuria (r=- 0.526, p=0.002). Plasma adiponectin levels in patients with proteinuria (n=31; 3.91+/-2.57 microg/mL) were significantly lower than those without proteinuria (n=33; 10.15+/-1.97 microg/mL) (p<0.001). After the treatment period, adiponectin levels significantly increased (p<0.001) and proteinuria, plasma insulin, and HOMA indexes significantly decreased in treatment group (p<0.001, p<0.001, p<0.001, respectively). The results suggest that adiponectin is inversely correlated with proteinuria and treatment with peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist rosiglitazone both corrects proteinuria and increases the low adiponectin levels in diabetic patients.

Adipocytes↗
PubMed2004

Plasma adiponectin concentration in relation to severity of coronary atherosclerosis and cardiovascular risk factors in middle-aged men.

UNLABELLED: Adiponectin, an adipocyte-derived protein, seems to be a link between obesity, insulin resistance, and atherosclerosis. The present study investigated the association between adiponectin and coronary artery disease in middle-aged men. MATERIAL AND METHODS: We examined 48 men (aged 40-60) with angiographically confirmed coronary atherosclerosis and 19 healthy men, matched by age, as a control group. Concentrations of glucose and lipids were estimated with enzymatic methods. Plasma level of adiponectin, total and free testosterone, estradiol, estrone, DHEA-S, and insulin were estimated with RIA commercial kits. RESULTS: Men with coronary atherosclerosis had lower plasma adiponectin level than controls (16.2+/-9.2 vs 20.5+/-6.7 microg/mL; p<0.05). However, after including BMI and waist as covariate data in ANCOVA, the difference in adiponectin levels between men with CAD and controls lost statistical significance (respectively for BMI and waist: p=0.4 and p=0.7). Moreover, although not significant, adiponectin levels decreased as a function of the number of significantly narrowed coronary arteries. In a priori comparison the lowest adiponectin plasma concentration was in men with three-vessel coronary artery disease (14.3+/-9.8 microg/mL) and the high-est in controls (20.5+/-6.8 microg/mL; p=0.09). Adiponectin plasma level correlated negatively (p<0.05) with BMI, waist, percentage of total fat, fasting-insulin-resistance index (FIRI), total cholesterol and triglycerides, and positively with quantitative insulin sensitivity check index (QUICKI), HDL cholesterol, total testosterone, and total testosterone/estradiol ratio. CONCLUSIONS: Our data suggest that low plasma adiponectin level is connected with insulin resistance syndrome and atherogenic lipid profile. It seems that adiponectin plays a role in pathogenesis of coronary atherosclerosis, especially in obese and insulin-resistant subjects.

Adiponectin↗
PubMed2003

Plasma adiponectin and hyperglycaemia in diabetic patients.

The insulin-sensitising adipose hormone adiponectin is reduced in type 2 diabetic patients. We assessed the relationships between plasma adiponectin and chronic hyperglycaemia. Adiponectin levels and glycated haemoglobin (HbA1c) were measured at enrolment and after 90 days in 16 patients with type 2 diabetes aged (mean +/- SEM) 63.0 +/- 0.6 years, with body mass index (BMI) 30.2 +/- 0.5 kg/m2 and HbA1c concentration 7.4 +/- 0.1%, who did not modify their hypoglycaemic treatment during the observation period. Furthermore, plasma adiponectin was measured in 29 adult patients with type 1 diabetes and compared with 29 control subjects matched for sex, age, BMI, waist circumference and bioimpedance-estimated fat mass. In type 2 diabetic patients at enrolment, adiponectin concentration correlated with BMI (r = -0.46; p < 0.05), but not with HbA1c. During the prospective observation, variations of adiponectin showed a significant correlation with variations of BMI (r = -0.47; p < 0.01), but not with variations of HbA1c concentration. These results were confirmed by multivariate analysis after adjustment for sex and age. Adiponectin levels in type 1 diabetic patients (380.8 +/- 13.7 ng/ml in women, 192.5 +/- 13.9 ng/ml in men) were significantly (p < 0.05) higher than in control subjects (277.6 +/- 11.0 ng/ml in women, 102.7 +/- 5.1 ng/ml in men); plasma adiponectin correlated significantly with BMI and waist circumference, but not with HbA1c. In conclusion, the reduction of plasma adiponectin levels in type 2 diabetic patients does not appear to be determined by chronic hyperglycaemia. Adiponectin levels are increased in type 1 diabetes, but this phenomenon is not attributable to differences in nutritional status or body composition.

Adiponectin↗
PubMed2006

Biovariability of plasma adiponectin.

BACKGROUND: Adiponectin is a cytokine produced by adipose tissue with insulin sensitising and anti-atherosclerotic effects. Low plasma adiponectin levels are used as a marker of the metabolic syndrome and incipient type 2 diabetes. METHODS: We carried out a series of studies to determine the short- and long-term variability of plasma adiponectin levels, including diurnal and post-prandial changes. These investigations also included examining the effect of frozen storage on plasma adiponectin levels. RESULTS: A nested study in 10 overweight subjects with the metabolic syndrome and 10 age- and sex-matched controls showed intra-subject variation in adiponectin levels over a 30-day period of 12.2% and 18.8%, respectively, equivalent to reference change values of 1.7 and 3.6 microg/mL. In non-obese subjects, plasma adiponectin levels varied minimally over a 15-month period (baseline, 8.3+/-2.9 microg/mL vs. +15 months, 8.2+/-3.0 microg/mL, p=0.95) and showed only minor diurnal and post-prandial changes (pre-meal, 8.2+/-3.0 microg/mL vs. 3 h post-prandial, 8.3+/-3.1 microg/mL, p=0.60). The adiponectin assay had an intra-assay variation of 8.8%, with storage at -30 degrees C for 33 months or three cycles of freezing and thawing having no discernible effect on adiponectin levels. CONCLUSIONS: These results demonstrate that plasma adiponectin levels have relatively low biovariability and that adiponectin can be sampled fasting or non-fasting to provide a reliable marker of insulin resistance and incipient type 2 diabetes.

Adiponectin↗
PubMed2004

Correlates of adiponectin and the leptin/adiponectin ratio in obese and non-obese children.

Adiponectin is an adipocyte secreted protein that has been reported to increase fatty acid oxidation and improve insulin sensitivity. Our aim was to study the relationship between adiponectin and leptin, body fat, insulin and lipoproteins in obese compared to non-obese children matched for age and gender. Adiponectin serum concentrations were significantly lower in the obese compared to the non-obese children (9.1+/-3.7 vs 17.1+/-12.3 microg/ml, p <0.05), in contrast to serum leptin concentrations which were greater in the obese compared to the non-obese subjects (31.8+/-11.1 vs 8.2+/-5.7 ng/ml, p <0.001). When considered as a single group to assess adiponectin concentrations over a spectrum of body size, adiponectin values correlated inversely with body weight (r = -0.33, p <0.05) and BMI (r = -0.35, p <0.05). Adiponectin values correlated directly with HDL-C (r = 0.47, p <0.005), but not with total cholesterol, IGF-I, or leptin binding activity. Since leptin and adiponectin change inversely in relation to BMI, the leptin/adiponectin (L/A) ratio was determined as a potential index relating adiposity to the development of complications of obesity. The L/A ratio was eight-fold greater in the obese compared to the non-obese children, and correlated more strongly with BMI (r = 0.779, p <0.0001) and with HDL-C (r = -0.53, p <0.001), than did adiponectin alone. The L/A ratio also correlated significantly with triceps skinfold thickness (TSF) (r = 0.77, p <0.001) and percent body fat (r = 0.79, p <0.0001) in non-obese children. These data suggest that adiponectin concentrations are already differentially regulated in childhood obesity. The index of increased leptin concentration corrected by reduced adiponectin values (L/A ratio) merits investigation as a marker for morbidities associated with childhood obesity.

Adiponectin↗
PubMed2004

Serum adiponectin levels in adults with Prader-Willi syndrome are independent of anthropometrical parameters and do not change with GH treatment.

OBJECTIVE: Obesity and growth hormone (GH) deficiency are common in Prader-Willi syndrome (PWS) and these patients are at risk of metabolic diseases in adult life and of reduced life span. Low adiponectin values are associated with obesity and the metabolic syndrome. We therefore found it of interest to measure adiponectin levels in PWS. PATIENTS AND METHODS: 17 adults, nine men and eight women, 17 to 32 years of age, with a mean body mass index (BMI) of 35+/-3.2 kg/m2 participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin) for six months, and subsequently all received GH for 12 months. At baseline, serum total adiponectin levels in the PWS patients were compared with 25 lean and 34 obese controls. Body composition and various metabolic parameters, including adiponectin, were studied every six months in the PWS group. RESULTS: Serum adiponectin levels in PWS subjects were significantly lower (P<0.001) compared with lean and significantly higher (P<0.001) compared with obese controls. In PWS patients, no correlation was found between adiponectin and anthropometrical parameters or measures of insulin sensitivity (e.g. fasting insulin and insulin sensitivity as estimated by the homeostasis model assessment), or between adiponectin and IGF binding protein-1 or IGF-I. Adiponectin did not change during GH intervention. CONCLUSION: In this study of adults with PWS serum total adiponectin levels were higher than in controls with simple obesity and were independent of anthropometrical parameters. In accordance with this the metabolic syndrome is not necessarily present in all PWS patients. Correction of GH deficiency had no effect on serum adiponectin levels.

Adiponectin↗
PubMed2006

Effect of DHEA-sulfate on adiponectin gene expression in adipose tissue from different fat depots in morbidly obese humans.

OBJECTIVE: A growing body of studies has demonstrated the inverse relationship between DHEA-sulfate (DHEA-S) and the pathological alterations associated with the metabolic syndrome. However, the mechanism by which DHEA-S treatment operates has not been elucidated completely. Adiponectin, an adipose-specific protein, is thought to have anti-diabetic and anti-atherosclerotic properties. Because fat depots differ in the impact of their relationship with the undesirable consequences of obesity, the aim of the present study was to investigate the effect of DHEA-S on adiponectin expression in both s.c. and visceral tissues in a morbidly obese population. DESIGN AND METHODS: We studied the in vitro expression of the adiponectin gene from paired biopsies of human visceral and s.c. adipose tissue, obtained from men and women (body mass index = 48.68+/- 7.43 kg/m2). Adipocytes were incubated for 24 h with or without DHEA-S. Adiponectin mRNA was measured by reverse transcription-quantitative PCR. RESULTS: In this population, DHEA-S plasma values were 141 +/- 105 microg/100 ml. Serum adiponectin values were under normal ranges. In basal conditions, s.c. tissue expressed higher amounts (58%) of adiponectin mRNA than visceral tissue (P = 0.027). Adiponectin expression was differentially regulated in the two depots by DHEA-S. There was a significant increase in adiponectin expression specifically in the visceral tissue (P = 0.020), but no significant effect of DHEA-S on the s.c. tissue (P = 0.738). CONCLUSIONS: In the present study, for the first time in humans, we have shown that DHEA-S treatment is a strong upregulator of adiponectin gene expression in omental adipocytes, suggesting that the positive effects observed by DHEA-S treatment in humans suffering from metabolic syndrome could be exerted through overexpression of adiponectin in the visceral depot.

Adipocytes↗
PubMed2006

Impaired expression of cardiac adiponectin in leptin-deficient mice with viral myocarditis.

A mouse model of encephalomyocarditis (EMC) virus-induced myocarditis was used to investigate the expression of adiponectin in damaged cardiomyocytes. We intraperitoneally injected EMC virus into leptin-deficient ob/ob (OB) mice and wild-type (WT) mice. OB mice were divided into two subgroups consisting of mice with no intervention and mice receiving leptin replacement starting simultaneously with viral inoculation. We determined differences in heart weight, cardiac histological score, numbers of infiltrating and apoptotic cells in the myocardium, expression levels of adiponectin and TNF-alpha mRNA in the heart, adiponectin immunoreactivity in myocytes, adiponectin and TNF-alpha concentrations in the heart, and immunoreactivity of adiponectin receptors in myocytes between OB mice and WT mice. There was significantly decreased adiponectin mRNA expression, immunoreactivity, and protein level in the heart, and reduced immunoreactivity of adiponectin receptor 1 in myocytes from OB mice on days 4 and 8 after viral inoculation as compared with those in WT mice, together with increased cardiac weight, severe inflammatory myocardial damage, and increased levels of cardiac TNF-alpha mRNA and protein. Replacement of leptin in OB mice inhibited the development of severe myocarditis through augmentation of adiponectin mRNA, immunoreactivity, and protein level, increased adiponectin receptor 1 immunoreactivity in myocytes, and suppressed levels of TNF-alpha mRNA and protein. These results suggest that impaired expression of cardiac adiponectin may contribute to the progression of viral myocarditis through enhanced expression of TNF-alpha under a leptin-deficient condition.

Adiponectin↗
PubMed2001

PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein.

Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPARgamma ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-alpha, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-alpha. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-alpha on the adiponectin promoter.

3T3 Cells↗
PubMed2003

Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes.

Adiponectin is an abundant adipocyte-derived plasma protein with anti-atherosclerotic and insulin-sensitizing properties that suppresses hepatic glucose production and enhances glucose uptake into skeletal muscle. To characterize the potential effects of adiponectin on glucose uptake into adipose cells, we incubated isolated epididymal rat adipocytes with the globular domain of recombinant adiponectin purified from an E. coli expression system. Globular adiponectin increased glucose uptake in adipocytes without stimulating tyrosine phosphorylation of the insulin receptor or insulin receptor substrate-1, and without enhancing phosphorylation of Akt on Ser-473. Globular adiponectin further enhanced insulin-stimulated glucose uptake at submaximal insulin concentrations and reversed the inhibitory effect of tumor necrosis factor-alpha on insulin-stimulated glucose uptake. Cellular treatment with globular adiponectin increased the Thr-172 phosphorylation and catalytic activity of AMP-activated protein kinase and enhanced the Ser-79 phosphorylation of acetyl CoA carboxylase, an enzyme downstream of AMP kinase in adipose cells. Inhibition of AMP kinase activation using two pharmacological inhibitors (adenine 9-beta-D-arabinofuranoside and compound C) completely abrogated the increase in glucose uptake stimulated by globular adiponectin, indicating that AMP kinase is integrally involved in the adiponectin signal transduction pathway. Coupled with recent evidence that the effects of adiponectin are mediated via AMP kinase activation in liver and skeletal muscle, the findings reported here provide an important mechanistic link in the signaling effects of adiponectin in diverse metabolically responsive tissues.

AMP-Activated Protein Kinases↗
PubMed2004

Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes.

OBJECTIVE: Adiponectin and resistin, two recently discovered adipocyte-secreted hormones, may link obesity with insulin resistance and/or metabolic and cardiovascular risk factors. We performed a cross-sectional study to investigate the association of adiponectin and resistin with inflammatory markers, hyperlipidemia, and vascular reactivity and an interventional study to investigate whether atorvastatin mediates its beneficial effects by altering adiponectin or resistin levels. RESEARCH DESIGN AND METHODS: Associations among vascular reactivity, inflammatory markers, resistin, and adiponectin were assessed cross-sectionally using fasting blood samples obtained from 77 subjects who had diabetes or were at high risk to develop diabetes. The effect of atorvastatin on adiponectin and resistin levels was investigated in a 12-week-long randomized, double-blind, placebo-controlled study. RESULTS: In the cross-sectional study, we confirm prior positive correlations of adiponectin with HDL and negative correlations with BMI, triglycerides, C-reactive protein (CRP), and plasma activator inhibitor (PAI)-1 and report a negative correlation with tissue plasminogen activator. The positive association with HDL and the negative association with PAI-1 remained significant after adjusting for sex and BMI. We also confirm prior findings of a negative correlation of resistin with HDL and report for the first time a positive correlation with CRP. All of these associations remained significant after adjusting for sex and BMI. No associations of adiponectin or resistin with any aspects of vascular reactivity were detected. In the interventional study, atorvastatin decreased lipid and CRP levels, but adiponectin and resistin were not specifically altered. CONCLUSIONS: We conclude that adiponectin is significantly associated with inflammatory markers, in part, through an underlying association with obesity, whereas resistin's associations with inflammatory markers appear to be independent of BMI. Lipid profile and inflammatory marker changes produced by atorvastatin cannot be attributed to changes of either adiponectin or resistin.

Adiponectin↗