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PubMed2006

Comparison of serum high-molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzyme-linked immunosorbent assay to detect HMW adiponectin.

Adiponectin (Acrp30), an adipocyte-derived protein, exists in serum as a trimer, a hexamer, and a high-molecular weight (HMW) form, including 12-18 subunits. Because HMW adiponectin may be biologically active, we measured it in serum using a novel enzyme-linked immunosorbent assay (ELISA) confirmed by gel filtration chromatography that the ELISA detected mainly adiponectin with 12-18 subunits, and we compared HMW with total adiponectin concentration in patients with type 2 diabetes. We next investigated the relationship between serum HMW and coronary artery disease (CAD) in 280 consecutive type 2 diabetic patients, including 59 patients with angiographically confirmed CAD. Total adiponectin was measured in serum by a commercially available ELISA. Like serum total adiponectin, HMW adiponectin correlated positively with HDL cholesterol and negatively with triglyceride, insulin sensitivity, creatinine clearance, and circulating inflammatory markers. Total and HMW adiponectin were significantly higher in women than in men, as was the HMW-to-total adiponectin ratio. Serum HMW and the HMW-to-total adiponectin ratio were significantly lower in men with than without CAD (P < 0.05, respectively). In women, the ratio, but neither total nor HMW adiponectin, tended to be lower when CAD was present. In conclusion, determination of HMW adiponectin, especially relative to total serum adiponectin, is useful for evaluating CAD in type 2 diabetic patients.

Adiponectin↗
PubMed2006

Identification of adiponectin and its receptors in human osteoblast-like cells and association of T45G polymorphism in exon 2 of adiponectin gene with lumbar spine bone mineral density in Korean women.

OBJECTIVE: The role of adiponectin in bone metabolism has been recently reported in in vitro and in vivo studies. There has been no report on the association of adiponectin gene polymorphism and bone mineral density (BMD). Therefore, we investigated whether two single nucleotide polymorphisms (SNPs), T45G and G276T, in the adiponectin gene were related to BMD in Koreans. We also report on the identification of adiponectin and its receptors 1 and 2 in human osteoblast-like cell lines. PATIENTS AND MEASUREMENTS: MG-63 cells were cultured and osteogenic and adipogenic differentiations from human mesenchymal stem cells (hMSCs) were performed. RNA was then extracted from the cultured cells and reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using primers for adiponectin and for the adiponectin receptor genes. In 249 female and 80 male subjects, measurements were made of their lumbar spine and femoral neck BMDs, and biochemical markers of bone turnover. The genotyping of the T45G polymorphism in exon 2 and the G276T polymorphisms in intron 2 in the adiponectin gene was performed using an allelic discrimination assay with a TaqMan probe. Analyses were performed separately in each cohort. RESULTS: We found that the mRNAs for adiponectin and for adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) were expressed in the MG-63 cells. Sequencing of the PCR products revealed that they were identical to human adiponectin, AdipoR1 and AdipoR2, respectively. mRNAs for adiponectin, AdipoR1 and AdipoR2 were also expressed in the osteoblastic and adipogenic cell lines differentiated from hMSCs. For the polymorphism study, the frequencies of T45G and G276T in the adiponectin gene were in compliance with Hardy-Weinberg equilibrium and the two polymorphisms were in complete linkage disequilibrium (D' = -1.0, P < 0.001). In the female cohort, subjects with G alleles at the T45G locus had significantly lower lumbar spine BMD than those subjects with the TT genotype. Although BMD levels showed no association with the G276T locus, the GT genotype group showed significantly higher urine deoxypyridinoline levels than other genotype groups. In the male cohort, no association was observed between adiponectin genotypes and BMD levels. CONCLUSIONS: We observed the expression of adiponectin, AdipoR1 and AdipoR2 in the MG-63 cell line and the osteoblastic cell line differentiated from hMSCs. T45G polymorphism in exon 2 of the adiponectin gene is associated with lumbar spine BMD and G276T polymorphism in intron 2 of the adiponectin gene is associated with the urine deoxypyridinoline level in Korean women. Additional studies are needed to elucidate the precise contribution of adiponectin to bone mineral metabolism.

Absorptiometry, Photon↗
PubMed2005

The effects of exercise and adipose tissue lipolysis on plasma adiponectin concentration and adiponectin receptor expression in human skeletal muscle.

OBJECTIVE: It has been suggested that adiponectin regulates plasma free fatty acid (FFA) clearance by stimulating FFA uptake and/or oxidation in muscle. We aimed to determine changes in plasma adiponectin concentration and adiponectin receptor 1 and 2 mRNA expression in skeletal muscle during and after prolonged exercise under normal, fasting conditions (high FFA trial; HFA) and following pharmacological inhibition of adipose tissue lipolysis (low FFA trial; LFA). Furthermore, we aimed to detect and locate adiponectin in skeletal muscle tissue. METHODS: Ten subjects performed two exercise trials (120 min at 50% VO(2max)). Indirect calorimetry was used to determine total fat oxidation rate. Plasma samples were collected at rest, during exercise and during post-exercise recovery to determine adiponectin, FFA and glycerol concentrations. Muscle biopsies were taken to determine adiponectin protein and adiponectin receptor 1 and 2 mRNA expression and to localise intramyocellular adiponectin. RESULTS: Basal plasma adiponectin concentrations averaged 6.57+/-0.7 and 6.63+/-0.8 mg/l in the HFA and LFA trials respectively, and did not change significantly during or after exercise. In the LFA trial, plasma FFA concentrations and total fat oxidation rates were substantially reduced. However, plasma adiponectin and muscle adiponectin receptor 1 and 2 mRNA expression did not differ between trials. Immunohistochemical staining of muscle cross-sections showed the presence of adiponectin in the sarcolemma of individual muscle fibres and within the interfibrillar arterioles. CONCLUSION: Plasma adiponectin concentrations and adiponectin receptor 1 and 2 mRNA expression in muscle are not acutely regulated by changes in adipose tissue lipolysis and/or plasma FFA concentrations. Adiponectin is abundantly expressed in muscle, and, for the first time, it has been shown to be present in/on the sarcolemma of individual muscle fibres.

Adiponectin↗
PubMed2006

Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines.

AIMS/HYPOTHESIS: Pregnancy, a state of insulin resistance, is associated with elevated levels of cytokines and profound alterations in metabolism. Serum adiponectin, an adipokine with anti-inflammatory and insulin-sensitising properties, has been shown to be lower in patients with gestational diabetes mellitus, a state of greater insulin resistance than normal pregnancies. Hypothesising that the human placenta is a source of adiponectin, we investigated its expression and secretion, and the regulation by cytokines of adiponectin and its receptors. METHODS: Real-time RT-PCR, radioimmunoassay, Western blotting, radioligand binding and immunofluorescent analyses were applied to demonstrate the expression, secretion and functionality of placental adiponectin. RESULTS: Adiponectin gene expression and protein were found in the human term placenta, with expression primarily in the syncytiotrophoblast. RIA of conditioned media from explant experiments revealed that the placenta can secrete adiponectin in vitro. Addition of conditioned media to HEK-293 cells transfected with the gene for adiponectin receptor-1 (ADIPOR1) altered the phosphorylation status of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase, an effect abolished after preabsorption with adiponectin antibody. Cytokines, including TNF-alpha, IFN-gamma, IL-6 and leptin, differentially modulated placental adiponectin receptors as well as adiponectin gene expression and secretion. Interestingly, in placentae from women with gestational diabetes mellitus, we observed significant downregulation of adiponectin mRNA, significant upregulation of ADIPOR1 expression, and a non-significant increase in ADIPOR2 expression. CONCLUSIONS/INTERPRETATION: Our results indicate that the human placenta produces and secretes adiponectin, and that adiponectin and its receptors are differentially regulated by cytokines and their expression altered in women with gestational diabetes mellitus. Collectively, our novel data suggest that adiponectin may play a role in adapting energy metabolism at the materno-fetal interface.

Adiponectin↗
PubMed2005

High adiponectin in chronic liver disease and cholestasis suggests biliary route of adiponectin excretion in vivo.

BACKGROUND/AIMS: Models of fatty liver diseases and fibrosis suggest a hepatoprotective effect of adiponectin, an adipocyte-derived hormone with antidiabetic, antiobesity, antiatherogenic and anti-inflammatory effects. METHODS: We studied adiponectin serum levels in 111 chronic liver disease (CLD) patients and 226 healthy controls and the impact of cholestasis on adiponectin by bile duct ligation experiments in mice. RESULTS: Adiponectin was significantly elevated in CLD, and correlated with stage of liver cirrhosis, liver cell injury, e.g. aminotransferase activity, and inflammatory markers, but not with liver synthesis capacity, insulin sensitivity (HOMA index) or clinical complications. As patients with biliary liver diseases and cholestasis exhibited the highest adiponectin levels, we experimentally investigated a potential biliary route of adiponectin excretion. Following bile duct ligation in mice adiponectin levels rapidly increased without affecting hepatic adiponectin gene expression. Also, adiponectin was detectable in human bile. High adiponectin concentrations were associated with severe cholangitis and/or cholestasis on liver histology. CONCLUSIONS: Adiponectin is elevated in chronic liver disease and correlates with inflammation and liver damage. High adiponectin levels after bile duct ligation in mice and in human bile from cholestatic patients suggest that biliary secretion is involved in adiponectin clearance and that adiponectin could serve as a novel marker indicating cholestasis in liver cirrhosis.

Adiponectin↗
PubMed2005

Gene expression of adiponectin and adiponectin receptor 1 in type 2 diabetic rats and the relationship with the parameters of glucose and lipid metabolism.

In order to confirm whether the mRNA levels of adiponectin in adipose tissue and mRNA levels of AdipoR1 in the skeletal muscles were correlated with the serum parameters of glucose and lipid metabolism and to clarify the regulation of adiponectin receptor gene expression in diabetic states, serum adiponectin, mRNA levels of adiponectin in adipose tissue and mRNA levels of AdipoR1 in the skeletal muscles were examined in type 2 diabetic rats. The model of type 2 diabetes was prepared by feeding high fat diet and injecting low dosage of streptozotocin (STZ). The diabetic rats were screened out by oral glucose tolerance test. One group of type 2 diabetic rats received rosiglitazone. The serum adiponectin concentration was detected by using ELISA and mRNA levels were examined by RT-PCR. The serum adiponectin levels and mRNA levels of adiponectin in adipose tissue of type 2 diabetic rats were significantly decreased as compared with the normal control rats (P<0.05, P<0.01 respectively). No siglificant changes were observed in the expression of adiponectin receptor 1 in the skeletal muscle of type 2 diabetic rats. The mRNA levels of adiponectin in adipose tissue were reversely correlated with serum insulin (r=-0.66, P<0.05), triglyceride (r= -0.58, P<0.05), cholesterol (r=-0.49, P<0.05), interleukin-6 (r=-0.49, P<0. 05) and tumor necrosis factor (r= -0.43, P<0.05). The expression of adiponectin receptors was not altered in the skeletal muscle of Type 2 diabetic rats. The decreased serum adiponectin was caused by the decreased expression of adiponectin mRNA in adipose tissue rather than the adiponectin receptors in the skeletal muscle, which could be improved by rosiglitazone.

Adiponectin↗
PubMed2006

MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness.

Most rodent models of insulin resistance are accompanied by decreased circulating adiponectin levels. Adiponectin treatment improves the metabolic phenotype by increasing fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. Muscle IGF-I receptor (IGF-IR)-lysine-arginine (MKR) mice expressing dominant-negative mutant IGF-IRs in skeletal muscle are diabetic with insulin resistance in muscle, liver, and adipose tissue. Adiponectin levels are elevated in MKR mice, suggesting an unusual discordance between insulin resistance and adiponectin responsiveness. Therefore, we investigated the metabolic actions of adiponectin in MKR mice. MKR and ob/ob mice were treated both acutely (28 microg/g) and chronically (for 2 wk) with full-length adiponectin. Acute hypoglycemic effects of adiponectin were evident only in ob/ob mice but not in MKR mice. Chronic adiponectin treatment significantly improved both insulin sensitivity and glucose tolerance in ob/ob but not in MKR mice. Adiponectin receptor mRNA levels and adiponectin-stimulated phosphorylation of AMPK in skeletal muscle and liver were similar among MKR, wild-type, and ob/ob mice. Thus MKR mice are adiponectin resistant despite normal expression of adiponectin receptors and normal AMPK phosphorylation in muscle and liver. MKR mice may be a useful model for dissecting relationships between insulin resistance and adiponectin action in regulation of glucose homeostasis.

Adiponectin↗
PubMed2005

Adiponectin and resistin serum levels in women with polycystic ovary syndrome during oral glucose tolerance test: a significant reciprocal correlation between adiponectin and resistin independent of insulin resistance indices.

Polycystic ovary syndrome (PCOS) is associated with an increased incidence of insulin resistance (IR), obesity, and type 2 diabetes. Resistin, an adipocytokine, may represent a link between obesity, and these metabolic disorders. There is also evidence that inflammation is a hyperresistinemic state in humans, and cytokine induction of resistin may contribute to insulin resistance in endotoxemia, obesity, and other inflammatory states. In contrast, adiponectin, increases insulin sensitivity, improves glucose tolerance, inhibits inflammatory pathways, while adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis. We aimed to assess, in women with PCOS, whether there is a relationship between adiponectin and resistin and the indices of IR, and whether serum levels of these adipocytokines are altered by glucose-induced hyperinsulinaemia. Serum levels of resistin and adiponectin were measured at 0, 60, and 120 min during 75 g oral glucose tolerance test (OGTT), in 19 women with PCOS, age 36.3+/-11.4 years (mean+/-SD), body mass index (BMI) 29.3+/-7.7 kg/m2, and correlated with the indices of IR, such as HOMA-IR, QUICKI, and the insulin resistance index calculated from glucose and insulin levels obtained during OGTT. There was no change in resistin concentrations (7.31+/-4.58, 7.47+/-5.40, 7.22+/-5.12 pg/ml, at 0, 60, and 120 min of OGTT, respectively, P = 0.77), but there was an increase in adiponectin from 11.32+/-4.64 microg/ml at baseline to 14.78+/-7.41 microg/ml, at 120 min of OGTT (P < 0.01). The magnitude of the overall rise in adiponectin was greater from 60 to 120 min (from 12.31+/-5.72 to 14.78+/-7.41 microg/ml, P < 0.006). Neither resistin, nor adiponectin correlated with the indices of IR, lipids, or other hormonal parameters of the PCOS. There was, however, a significant negative correlation between serum resistin and adiponectin (P = 0.001). In conclusion, we observed a strong negative correlation between serum adiponectin and resistin, despite the lack of direct correlation with the indices of IR. Given the opposite effects of resistin and adiponectin on the inflammatory process, we speculate that relative proportion of adiponectin-to-resistin might potentially influence cardiometabolic risk in women with the PCOS independently of IR parameters. The observed increase in adiponectin during OGTT requires further study.

Adiponectin↗
PubMed2005

Adiponectin gene is expressed in multiple tissues in the chicken: food deprivation influences adiponectin messenger ribonucleic acid expression.

Adiponectin is a cytokine hormone originally found to be secreted exclusively by white adipose tissue. However, recent evidences suggest that adiponectin is also produced in brown adipose tissue and skeletal muscle. The present study investigated the expression of adiponectin mRNA in various tissues in the chicken. We also studied the effect of food deprivation on adiponectin gene expression in adipose tissue, liver, anterior pituitary gland, and diencephalon in the chicken. The open reading frame of chicken adiponectin cDNA consists of 735 nucleotides that were 65-68% homologous to various mammalian adiponectin cDNAs. The deduced amino acid sequence of chicken adiponectin contains 22 glycine-X-Y repeats (in which X and Y represent any amino acid) at the N-terminal end as found in the mammalian adiponectin. By RT-PCR and Northern analysis, we detected chicken adiponectin mRNA transcript in adipose tissue, liver, anterior pituitary gland, diencephalon, skeletal muscle, liver, kidney, ovary, and spleen but not in blood. Adiponectin mRNA expression in various tissues was quantitated using real-time quantitative PCR and found to be the highest in adipose tissue, followed by liver, anterior pituitary, diencephalon, kidney, and skeletal muscle. We also found that adiponectin mRNA quantity was significantly decreased after a 48-h food deprivation in adipose tissue, liver, and anterior pituitary gland but not in diencephalon. Our results provide novel evidence that, unlike mammals, adiponectin gene is expressed in several tissues in the chicken and that its expression is influenced by food deprivation.

Adiponectin↗
PubMed2005

A protective effect of adiponectin against oxidative stress in Japanese Americans: the association between adiponectin or leptin and urinary isoprostane.

Adiponectin, which is produced by adipose tissue, is thought to play an important role in inflammation. On the other hand, adiposity, or the hypertrophy of adipose tissue, has been reported to increase oxidative stress. Accordingly, the possibility exists that adiponectin, as well as leptin, influences oxidative stress, resulting in a proinflammatory state. However, the relationship between adiponectin and oxidative stress is unclear. We examined 259 Japanese Americans living in Hawaii who were diagnosed as having normal glucose tolerance (NGT), impaired glucose tolerance, or diabetes by a 75-g oral glucose tolerance test. First, we measured their serum adiponectin, leptin, and high-sensitivity C-reactive protein levels as markers of inflammation, and urinary 8-iso-protaglandin F(2 alpha) (isoprostane) as a relevant marker of oxidative stress. We investigated the relationship between adiponectin or leptin and isoprostane among these subjects. In the diabetic subjects, the adiponectin and leptin levels were significantly lower and higher, respectively, than among the NGT subjects. Urinary isoprostane levels tended to decrease significantly after a rise in adiponectin levels (P = .014) among the NGT subjects. Next, we investigated the association between the 2 adipocytokines and isoprostane by regression models. Adiponectin was negatively but significantly associated with urinary isoprostane levels adjusted for age, gender, and smoking status, whereas leptin was positively and significantly correlated with urinary isoprostane levels (P = .014 and .004, respectively). With respect to adiponectin, this association was attenuated but still significant when further adjustments were made for waist-to-hip ratio, body mass index, percent body fat, C-reactive protein levels, glucose tolerance status, or homeostasis model assessment. In conclusion, this study suggests that adiponectin and leptin might be associated with oxidative stress levels. These results also suggest the possibility that adiponectin might modulate oxidative stress, leading to antidiabetic and anti-arteriosclerotic effects.

Adiponectin↗
PubMed2005

Common polymorphisms (single-nucleotide polymorphisms SNP+45 and SNP+276) of the adiponectin gene regulate serum adiponectin concentrations and blood pressure in young Finnish men.

Epidemiologic studies have shown that serum level of adiponectin, a circulating protein secreted by adipocytes, predicts the risk of type 2 diabetes and cardiovascular events. Two single-nucleotide polymorphisms (SNPs) at the adiponectin locus (T45G or G276T) of the adiponectin gene (APM1) have been associated with insulin resistance, low serum adiponectin levels, and diabetes. In the present study, the association of these polymorphisms with serum adiponectin level and insulin resistance-associated risk factors was investigated. To this aim, SNP+45 and SNP+276 of APM1 were genotyped in 252 young Finnish men. Serum adiponectin level (p < 0.001) and diastolic blood pressure (p = 0.031) were significantly higher in subjects with the T276T genotype of APM1 compared to those with the G276T or G276G genotypes. Mean diastolic blood pressure among the T276T subjects was 80 mmHg and that in subjects with the G276G and G276T genotypes below 75 mmHg. An interaction between triglycerides, diastolic blood pressure, quantitative insulin sensitivity check index, and SNP276 with regard to serum adiponectin level was found. After adjustment for other covariates, the interaction between triglycerides and SNP276 remained statistically significant (p = 0.009). Among subjects with the T276T genotype, an increase in triglyceride level was associated with a decrease in adiponectin concentration. This result was not observed in other genotype groups. SNP+45 was not significantly related to serum adiponectin concentration, but high-density lipoprotein (HDL) cholesterol tended to be higher in subjects with the T45T genotype (p = 0.051) compared to subjects with the X45G genotype. In conclusion, the T276T genotype of the adiponectin gene was associated with elevated serum adiponectin level and diastolic blood pressure among young Finnish men.

Adiponectin↗
PubMed2007

Serum concentrations of adiponectin and characterization of adiponectin protein complexes in dogs.

OBJECTIVE: To assess serum concentrations of adiponectin and characterize adiponectin protein complexes in healthy dogs. ANIMALS: 11 healthy dogs. PROCEDURES: Sera collected from 10 dogs were evaluated via velocity sedimentation and ultracentrifugation, SDS-PAGE, western immunoblotting, and radioimmunoassay. Visceral adipose tissue (approx 90 g) was collected from the falciform ligament of a healthy dog undergoing elective ovariohysterectomy, and adiponectin gene expression was assessed via a real-time PCR procedure. RESULTS: Adiponectin gene expression was detected in visceral adipose tissue. Serum adiponectin concentrations ranged from 0.85 to 1.5 microg/mL (mean concentration, 1.22 microg/mL). In canine serum, adiponectin was present as a multimer, consisting of a low-molecular-weight complex (180 kd); as 3 (180-, 90-, and 60-kd) complexes under denaturing conditions; as 2 (90- and 60-kd) complexes under reducing conditions; and as a dimer, a monomer, and globular head region (60, 30, and 28 kd, respectively) under reducing-denaturing conditions. It is likely that adiponectin also circulates as a high-molecular-weight (360- to 540-kd) complex in canine serum, but resolution of this complex was not possible via SDS-PAGE. CONCLUSIONS AND CLINICAL RELEVANCE: After exposure to identical experimental conditions, adiponectin protein complexes in canine serum were similar to those detected in human and rodent sera. Circulating adiponectin concentrations in canine serum were slightly lower than concentrations in human serum. Adiponectin gene expression was identified in canine visceral adipose tissue. Results suggest that adiponectin could be used as an early clinical marker for metabolic derangements, including obesity, insulin resistance, and diabetes mellitus in dogs.

Adiponectin↗
PubMed2006

Effects of exercise on adiponectin and adiponectin receptor levels in rats.

Adiponectin reportedly reduces insulin-resistance. Exercise has also been shown to lessen insulin-resistance, though it is not known whether exercise increases levels of adiponectin and/or its receptors or whether its effects are dependent on exercise intensity and/or frequency. Catecholamine levels have been shown to increase during exercise and to fluctuate based on exercise intensity and duration. In light of this information, we examined the effects of exercise on catecholamine, adiponectin, and adiponectin receptor levels in rats. Our data showed that blood adiponectin levels increased by 150% in animals that exercised at a rate of 30 m/min for 60 min 2 days per week, but not 5 days, per week; no such increase was observed in rats that exercised at a rate of 25 m/min for 30 min. The effects of exercise on adiponectin receptor mRNA were variable, with adiponectin receptor 1 (AdipoR1) levels in muscle increasing up to 4 times while adiponectin receptor 2 (AdipoR2) levels in liver fell to below half in response to exercise at a rate of 25 m/min for 30 min 5 days per week. We also observed that urinary epinephrine levels and plasma lipids were elevated by exercise at a rate of 25 m/min for 30 min 2 days per week. Exercise frequency at a rate of 25 m/min for 30 min correlated with AdipoR1 and AdipoR2 mRNA expression in the muscle and liver, respectively (r=0.640, p<0.05 and r=-0.808, p<0.0005, respectively). Urinary epinephrine levels correlated with AdipoR2 mRNA expression in liver tissues (r=-0.664, p<0.05) in rats that exercised at a rate of 25 m/min for 30 min. Thus, exercise may regulate adiponectin receptor mRNA expression in tissues, which might cause increases in glucose uptake and fatty acid oxidation in the muscle. The effect of exercise on adiponectin levels depends on the specific conditions of the exercise.

Adiponectin↗
PubMed2006

APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function.

Adiponectin, also known as Acrp30, is an adipose tissue-derived hormone with anti-atherogenic, anti-diabetic and insulin sensitizing properties. Two seven-transmembrane domain-containing proteins, AdipoR1 and AdipoR2, have recently been identified as adiponectin receptors, yet signalling events downstream of these receptors remain poorly defined. By using the cytoplasmic domain of AdipoR1 as bait, we screened a yeast two-hybrid cDNA library derived from human fetal brain. This screening led to the identification of a phosphotyrosine binding domain and a pleckstrin homology domain-containing adaptor protein, APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding (PTB) domain and leucine zipper motif). APPL1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. Overexpression of APPL1 increases, and suppression of APPL1 level reduces, adiponectin signalling and adiponectin-mediated downstream events (such as lipid oxidation, glucose uptake and the membrane translocation of glucose transport 4 (GLUT4)). Adiponectin stimulates the interaction between APPL1 and Rab5 (a small GTPase) interaction, leading to increased GLUT4 membrane translocation. APPL1 also acts as a critical regulator of the crosstalk between adiponectin signalling and insulin signalling pathways. These results demonstrate a key function for APPL1 in adiponectin signalling and provide a molecular mechanism for the insulin sensitizing function of adiponectin.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Adiponectin and adiponectin receptors.

Metabolic syndrome is thought to result from obesity and obesity-linked insulin resistance. Obesity in adulthood is characterized by adipocyte hypertrophy. Adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active "adipokines."Heterozygous peroxisome proliferator-activated receptor-gamma knockout mice were protected from high-fat diet induced obesity, adipocyte hypertrophy, and insulin resistance. Systematic gene profiling analysis of these mice revealed that adiponectin/Acrp30 was overexpressed. Functional analyses including generation of adiponectin transgenic or knockout mice have revealed that adiponectin serves as an insulin-sensitizing adipokine. In fact, obesity-linked down-regulation of adiponectin was a mechanism whereby obesity could cause insulin resistance and diabetes. Recently, we have cloned adiponectin receptors in the skeletal muscle (AdipoR1) and liver (AdipoR2), which appear to comprise a novel cell-surface receptor family. We showed that AdipoR1 and AdipoR2 serve as receptors for globular and full-length adiponectin and mediate increased AMP-activated protein kinase, peroxisome proliferator-activated receptor-alpha ligand activities, and glucose uptake and fatty-acid oxidation by adiponectin. Obesity decreased expression levels of AdipoR1/R2, thereby reducing adiponectin sensitivity, which finally leads to insulin resistance, the so-called "vicious cycle." Most recently, we showed that osmotin, which is a ligand for the yeast homolog of AdipoR (PHO36), activated AMPK via AdipoR in C2C12 myocytes. This may facilitate efficient development of adiponectin receptor agonists. Adiponectin receptor agonists and adiponectin sensitizers should serve as versatile treatment strategies for obesity-linked diseases such as diabetes and metabolic syndrome.

Adiponectin↗
PubMed2005

The adiponectin gene SNP+276G>T associates with early-onset coronary artery disease and with lower levels of adiponectin in younger coronary artery disease patients (age <or=50 years).

Adiponectin, an adipocyte-derived protein, is an essential modulator of insulin sensitivity and several studies suggest an important role of adiponectin in the processes leading to atherosclerosis, thus indicating the adiponectin gene as a potential candidate for coronary artery disease (CAD). In the present study we have studied the association between two single nucleotide polymorphisms (SNPs) (+45T>G and +276 G>T) of the adiponectin gene and CAD, looking also into the possible influence of these SNPs on adiponectin plasma levels. The SNPs were analysed in a first cohort of 595 subjects, 325 with CAD and 270 matched controls. We observed a significant association (p<0.001) between the SNP +276G>T in the adiponectin gene and CAD. In multivariate analysis, carriers of the +276G>T SNP had an odds ratio (OR) for CAD of 4.99 (p<0.0007). A strong interaction between the +276G>T SNP and age was also present (OR, 1.03; p<0.0001). The increase in CAD risk was most evident among individuals with early-onset CAD (age T SNP was analysed in a second cohort of CAD and controls. The difference between CAD and controls in the +276G>T SNP frequencies showed a similar trend as before, although not significant. The combination of the two cohorts (1,046 subjects: 580 CAD and 466 controls) showed a statistically significant association, particularly in CAD subjects with early-onset of disease. In addition, we confirmed that in younger CAD subjects the SNP was a significant determinant of lower levels of adiponectin. In view of these results, it could be speculated that the adiponectin gene variant, or a mutation in linkage with it, determines lower adiponectin gene expression, causing in turn an increased risk to develop insulin resistance, atherosclerosis and cardiovascular disease. The significant association of the adiponectin gene in subjects with early-onset CAD also suggests that that genetic factors for late-onset diseases may exert a greater influence in younger persons, when other risk factors are not as prevalent as in older age groups.

Adiponectin↗
PubMed2003

Induction of adiponectin gene expression in human myotubes by an adiponectin-containing HEK293 cell culture supernatant.

AIMS/HYPOTHESIS: Adiponectin, an adipocytokine known to be down-regulated in obesity-linked disorders, is considered to be a potential key mediator of insulin sensitivity. In this study, we asked whether adiponectin is able to regulate ten selected genes possibly associated with insulin sensitivity in human skeletal muscle cells. METHODS: To this end, we treated in vitro differentiated human myotubes with the culture supernatant of HEK293 cells stably transfected with human recombinant adiponectin and assessed gene expression by RT-PCR. Intracellular adiponectin protein was quantified by radioimmunoassay and visualized by Western blotting. RESULTS: In contrast to the control supernatant, the adiponectin-containing supernatant consistently induced expression of adiponectin mRNA in human myotubes from eight different donors (mean increase: 90-fold over control; n=8, p<0.001). This increase in mRNA was paralleled by a rise in intracellular adiponectin protein (mean increase: 8.3-fold over control; n=4, p<0.05). Expression of the other nine candidate genes was not altered. In human skin fibroblasts and HepG2 cells, the adiponectin-enriched supernatant did not induce relevant amounts of adiponectin mRNA. CONCLUSIONS/INTERPRETATION: In conclusion, we show here that adiponectin gene expression is specifically inducible in skeletal muscle cells.

Adiponectin↗
PubMed2005

Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males.

AIMS/HYPOTHESIS: It is well established that total systemic adiponectin is reduced in type 2 diabetic subjects. To date most studies have been concerned with the singular full-length protein or proteolytically cleaved globular domain. It is, however, apparent that the native protein circulates in serum as a lower molecular weight hexamer and as larger multimeric structures of high molecular weight (HMW). In this study we address the clinical significance of each form of the protein with respect to glucose tolerance. METHODS: Serum was obtained from 34 Indo-Asian male subjects (BMI 26.5+/-3.1; age 52.15+/-10.14 years) who had undertaken a 2-h oral glucose tolerance test. An aliquot of serum was fractionated using velocity sedimentation followed by reducing SDS-PAGE. Western blots were probed for adiponectin, and HMW adiponectin as a percentage of total adiponectin (percentage of higher molecular weight adiponectin [S(A)] index) was calculated from densitometry readings. Total adiponectin was measured using ELISA; leptin, insulin and IL-6 were determined using ELISA. RESULTS: Analysis of the cohort demonstrated that total adiponectin (r = 0.625, p = 0.0001), fasting insulin (r = -0.354, p = 0.040) and age (r = 0.567, p = 0.0001) correlated with S(A). S(A) showed a tighter, inverse correlation with 2-h glucose levels (r = -0.58, p = 0.0003) than total adiponectin (r = -0.38, p = 0.0001). CONCLUSIONS/INTERPRETATION: This study demonstrates the importance of the S(A) index as a better determinant of glucose intolerance than measurements of total adiponectin. Our findings suggest that HMW adiponectin is the active form of the protein.

Adiponectin↗