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PubMed2004

Serum adiponectin as a biomarker for in vivo PPARgamma activation and PPARgamma agonist-induced efficacy on insulin sensitization/lipid lowering in rats.

BACKGROUND: PPARgamma agonists ameliorate insulin resistance and dyslipidemia in type 2 diabetic patients. Adiponectin possesses insulin sensitizing properties, and predicts insulin sensitivity of both glucose and lipid metabolism. In diet-induced insulin resistant rats and ZDF rats, the current studies determined the correlation between PPARgamma agonist-upregulated fatty acid binding protein(FABP3) mRNA in adipose tissue and PPARgamma agonist-elevated serum adiponectin, and the correlation between PPARgamma agonist-elevated serum adiponectin and PPARgamma agonist-mediated efficacy in insulin sensitization and lipid lowering. RESULTS: Parallel groups of SD rats were fed a high fat/sucrose (HF) diet for 4 weeks. These rats were orally treated for the later 2 weeks with vehicle, either PPARgamma agonist GI262570 (0.2-100 mg/kg, Q.D.), or GW347845 (3 mg/kg, B.I.D). Rats on HF diet showed significant increases in postprandial serum triglycerides, free fatty acids (FFA), insulin, and area under curve (AUC) of serum insulin during an oral glucose tolerance test, but showed no change in serum glucose, adiponectin, and glucose AUC. Treatment with GI262570 dose-dependently upregulated adipose FABP3 mRNA, and increased serum adiponectin. There was a position correlation between adipose FABP3 mRNA and serum adiponectin (r = 0.7350, p < 0.01). GI262570 dose-dependently decreased the diet-induced elevations in triglycerides, FFA, insulin, and insulin AUC. Treatment with GW347845 had similar effects on serum adiponectin and the diet-induced elevations. There were negative correlations for adiponectin versus triglycerides, FFA, insulin, and insulin AUC (For GI262570, r = -0.7486, -0.4581, -0.4379, and -0.3258 respectively, all p < 0.05. For GW347845, r = -0.6370, -0.6877, -0.5512, and -0.3812 respectively, all p < 0.05). In ZDF rats treated with PPARgamma agonists pioglitazone (3-30 mg/kg, B.I.D.) or GW347845 (3 mg/kg, B.I.D.), there were also negative correlations for serum adiponectin versus glucose, triglycerides, FFA (for pioglitazone, r = -0.7005, -0.8603, and -0.9288 respectively; for GW347845, r = -0.9721, -0.8483, and -0.9453 respectively, all p < 0.01). CONCLUSIONS: This study demonstrated that (a) PPARgamma agonists improved insulin sensitivity and ameliorated dyslipidemia in HF fed rats and ZDF rats, which were correlated with serum adiponectin; (b) Serum adiponectin was positively correlated with adipose FABP3 mRNA in GI262570-treated rats. These data suggest that serum adiponectin can serve as a biomarker for both in vivo PPARgamma activation and PPARgamma agonist-induced efficacy on insulin resistance and dyslipidemia in rats.

Adiponectin↗
PubMed2005

Suppression of adiponectin gene expression by histone deacetylase inhibitor valproic acid.

Valproic acid (VPA) has been used for the treatment of epilepsy and bipolar disorders for more than 30 yr. Obesity and insulin resistance are common side effects of VPA treatment. Adiponectin is an adipocyte-derived protein that plays an important role in controlling insulin sensitivity and glucose homeostasis. In this report, we examined the effects of VPA on adiponectin gene expression in C57BL/6J mice and in differentiated 3T3-L1 adipocytes. VPA treatment significantly decreased adiponectin protein and mRNA levels in both mice and 3T3-L1 adipocytes. The adipocyte study showed that VPA inhibited adiponectin gene expression in a dose- and time-dependent manner. Repression of adiponectin expression by VPA occurred at the transcription level and correlated with inhibition of histone deacetylase activity. Therapeutic concentrations of VPA increased overall histone acetylation and increased adiponectin promoter-driven luciferase expression in fibroblasts, but decreased adiponectin promoter activity in differentiated 3T3-L1 adipocytes. VPA treatment decreased adipogenic transcription factor CCAAT/enhancer binding protein-alpha (C/EBPalpha) levels and binding of C/EBPalpha to the adiponectin promoter without altering the levels of peroxisome proliferator-activated receptor-gamma and steroid regulatory element binding protein-1. Furthermore, VPA did not suppress adiponectin gene expression in C/EBPalpha gene-deficient adipocytes that stably expressed exogenous peroxisome proliferator-activated receptor-gamma2. Together, these results demonstrate that histone deacetylase inhibitor VPA suppresses adiponectin gene expression in mature adipocytes. The study also provides evidence that diminished C/EBPalpha protein level and decreased binding at the adiponectin promoter mediate the inhibitory effects of VPA on adiponectin gene transcription.

3T3-L1 Cells↗
PubMed2003

Adiponectin in human cord blood: relation to fetal birth weight and gender.

Adiponectin is an adipocyte-derived plasma protein with insulin-sensitizing and antiatherosclerotic properties. The aim of this study was to examine whether adiponectin is present in human fetal blood, to define its association with fetal birth weight, and to evaluate whether dynamic changes in adiponectin levels occur during the early neonatal period. Cord blood adiponectin levels were extremely high (71.0 +/- 21.0 microg/ml; n = 51) compared with serum levels in children and adults and positively correlated with fetal birth weights (r = 0.4; P < 0.01). No significant differences in adiponectin levels were found between female and male neonates. In addition, there was no correlation between cord adiponectin levels and maternal body mass index, cord leptin, or insulin levels. Cord adiponectin levels were significantly higher compared with maternal levels at birth (61.1 +/- 19.0 vs. 17.6 +/- 4.9 microg/ml; P < 0.001; n = 17), and no correlation was found between cord and maternal adiponectin levels. There were no significant differences between adiponectin levels at birth and 4 d postpartum (61.1 +/- 19.0 vs. 63.8 +/- 22.0 microg/ml; n = 17). These findings indicate that adiponectin in cord blood is derived from fetal and not from placental or maternal tissues. The high adiponectin levels in newborns compared with adults may be due to lack of negative feedback on adiponectin production resulting from lack of adipocyte hypertrophy, low percentage of body fat, or a different distribution of fat depots in the newborns.

Adiponectin↗
PubMed2006

Adiponectin, adiposity, and insulin resistance in children and adolescents.

CONTEXT: Determinants of adiponectin and its association with insulin resistance (IR) are less well studied in youth than in adults. OBJECTIVES: The objective of the study was to describe, in youth, the age- and sex-specific distribution of adiponectin concentrations and the association with demographic, anthropometric, and lifestyle factors, parental diabetes, and markers of IR. DESIGN, SETTING, PARTICIPANTS: We studied 1632 French Canadian youth aged 9, 13, and 16 yr who participated in the Québec Child and Adolescent Health and Social Survey, a province-wide, school-based survey conducted in 1999. RESULTS: Boys had lower adiponectin concentrations than girls by 17% (P < 0.0001). At age 16 yr, mean adiponectin concentrations were 27.7% (boys, P < 0.0001) and 13.3% (girls, P < 0.0001) lower than at age 9 yr (p(interaction) = 0.009). Mean adiponectin decreased for every unit increase in body mass index (BMI) Z-score by 8.1% in boys and 11.2% in girls (P < 0.0001). Growth-related change in BMI explained half the age effect in boys and all the age effect in girls. Self-reported pubertal status, physical activity, smoking, and parental diabetes were not independently associated with adiponectin. Fasting insulin and homeostasis model assessment-IR were not associated with adiponectin concentration. However, the interaction of adiponectin and BMI Z-score was significant in a multiple regression model of fasting insulin. CONCLUSIONS: Male sex and changes in body fat may be major determinants of the decreasing adiponectin concentrations of growing youth, which are accompanied by a dissociation of adiponectin and markers of IR. The relationship between adiposity and markers of IR is attenuated in those with higher adiponectin concentrations, making adiponectin a potential intervention target or risk marker.

Adiponectin↗
PubMed2003

The role of the novel adipocyte-derived hormone adiponectin in human disease.

Adiponectin, also called GBP-28, apM1, AdipoQ and Acrp30, is a novel adipose tIssue-specific protein that has structural homology to collagen VIII and X and complement factor C1q, and that circulates in human plasma at high levels. It is one of the physiologically active polypeptides secreted by adipose tIssue, whose multiple functions have started to be understood in the last few Years.A reduction in adiponectin expression is associated with insulin resistance in some animal models. Administration of adiponectin has been accompanied by a reduction in plasma glucose and an increase in insulin sensitivity. In addition, thiazolidinediones, drugs that enhance insulin sensitivity through stimulation of the peroxisome proliferator-activated receptor-gamma, increase plasma adiponectin and mRNA levels in mice. On the other hand, this adipocyte protein seems to play a protective role in experimental models of vascular injury. In humans, adiponectin levels are inversely related to the degree of adiposity and positively associated with insulin sensitivity both in healthy subjects and in diabetic patients. Plasma adiponectin levels have been reported to be decreased in some insulin-resistant states, such as obesity and type 2 diabetes mellitus, and also in patients with coronary artery disease. On the contrary, chronic renal failure, type 1 diabetes and anorexia nervosa are associated with increased plasma adiponectin levels. Concentrations of plasma adiponectin have been shown to correlate negatively with glucose, insulin, triglyceride levels and body mass index, and positively with high-density lipoprotein-cholesterol levels and insulin-stimulated glucose disposal. Weight loss and therapy with thiazolidinediones increased endogenous adiponectin production in humans. Adiponectin increases insulin sensitivity by increasing tIssue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents in liver and muscle. This protein also suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis. In view of these data, it is possible that hypoadiponectinemia may play a role in the development of atherosclerotic vascular disease. In summary, the ability of adiponectin to increase insulin sensitivity in conjunction with its anti-inflammatory and anti-atherogenic properties have made this novel adipocytokine a promising therapeutic tool for the future, with potential applications in states associated with low plasma adiponectin levels.

Adipocytes↗
PubMed2005

Plasma adiponectin is decreased in nonalcoholic fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and is frequently associated with obesity and metabolic syndrome. The recently discovered hormone adiponectin is produced by adipose tissue, and low plasma adiponectin is considered a key factor in the development of the insulin resistance underlying metabolic syndrome. Animal studies suggest that adiponectin may protect against non-alcoholic steatohepatitis, but direct evidence in humans is lacking. We therefore conducted this study to assess the relationship between plasma adiponectin and nonalcoholic fatty liver disease to explore its role in the pathogenesis of this disease. DESIGN AND METHODS: We measured plasma adiponectin and anthropometric, biochemical, hormonal and metabolic correlates in a group of 17 NAFLD patients with diagnosis confirmed by biopsy, and 20 controls with comparable age, body-mass index and sex. Furthermore we compared plasma adiponectin in patients with simple steatosis and steatohepatitis. RESULTS: Plasma adiponectin was significantly lower in NAFLD patients than controls (5.93+/-0.45 vs 15.67+/-1.60ng/ml). Moreover, NAFLD patients were significantly more insulin resistant while having similar serum leptin. Adiponectin was similar in simple steatosis and in steatohepatitis (6.16+/-0.78 vs 5.69+/-0.49ng/ml). An inverse correlation was observed between adiponectin and homeostatic model assessment (HOMA) of insulin resistance (P = 0.008), while adiponectin did not correlate with serum transaminases and lipid values. CONCLUSIONS: These data support a role for low circulating adiponectin in the pathogenesis of NAFLD and confirm the strict association between reduced adiponectin production by adipose tissue, NAFLD and insulin resistance.

Adiponectin↗
PubMed2005

The association of plasma adiponectin levels with hypertensive retinopathy.

OBJECTIVE: Previous studies have demonstrated that low plasma adiponectin concentrations are associated with essential hypertension. It has also recently been shown that adiponectin plays an essential role in the modulation of angiogenesis. These data led us to hypothesize that adiponectin might contribute to end-organ damage in hypertension. METHODS: In the present study we have evaluated the relationship between plasma adiponectin concentrations and hypertensive retinopathy. One hundred and ten patients newly diagnosed with essential hypertension (EHT) (mean age, 46.79+/-5.0 years; body mass index (BMI), 26.47+/-2.23 kg/m(2); male/female ratio, 58/52) and 57 healthy normotensive control subjects (NT) (mean age, 46.84+/-5.4 years; BMI, 26.66+/-2.65 kg/m(2); male/female ratio, 33/24) were enrolled. RESULTS: Plasma adiponectin levels were significantly lower in EHT than in NT (P < 0.001). In addition, adiponectin concentrations were strongly correlated with systolic and diastolic blood pressures in EHT (r = -0.757, P < 0.001; r = -0.761, P < 0.001) while there was no correlation in the NT group. Plasma adiponectin in patients with grade 0 hypertensive retinopathy (n = 52) was significantly higher than that of the patients with grade 1 (n = 30) and 2 (n = 28) hypertensive retinopathy (P < 0.001 for each). Plasma adiponectin in patients with grade 0 hypertensive retinopathy was also significantly lower than that in the NT group (P < 0.001). The estimated threshold of plasma adiponectin concentration for hypertensive retinopathy was 17 microg/ml. This critical adiponectin level served largely to separate patients with retinopathy from those without. CONCLUSION: Our results have shown that plasma adiponectin concentrations decrease progressively with higher grades of hypertensive retinopathy even after correction for other atherogenic risk factors, suggesting that a critical adiponectin level is needed for the development of retinopathy.

Adiponectin↗
PubMed2005

The metabolism of isoforms of human adiponectin: studies in human subjects and in experimental animals.

OBJECTIVE: Little is known of the metabolism of different isoforms of adiponectin. We therefore (a) characterised the size distribution of human adiponectin in relation to gender, body composition and following a challenge with a fat meal or oral glucose in humans, and (b) studied the metabolism of isoforms of human adiponectin in rabbits. METHOD: Electrophoresis, blotting and chromatography were used to characterise human adiponectin in 36 healthy subjects, including 15 with at least two first-degree relatives with type 2 diabetes, before and after consumption of a fatty meal or glucose. The metabolism of column-fractionated human adiponectin was studied in rabbits, some of which were coinjected with insulin. RESULTS: Females had a higher proportion of high molecular weight (HMW) and hexameric adiponectin (P = 0.002 and 0.004 respectively), and a lower proportion of trimers (P < 0.0001) than males. Females also showed a strong negative relationship between body fat measures and the proportion of HMW adiponectin. There were no differences in isoforms between insulin-resistant and -sensitive subjects, or following oral glucose or a fat meal. Adiponectin in rabbits had an extravascular/intravascular ratio of 0.71, and a half-life (T1/2) of 14.3 h. Metabolism was not influenced by insulin or reduction of sulphydryl bonds. HMW and trimeric isoforms had a significantly different T1/2 of 13.0 and 17.5 h respectively (P < 0.05), and these isoforms did not interconvert in vivo. CONCLUSIONS: Human adiponectin is present as trimers, hexamers and HMW forms. Females had a higher proportion and absolute amount of HMW species compared with males, and female, but not male, subjects showed a strong negative relationship between measures of body fat, and the proportion of HMW species. These isoforms did not respond to challenge in man with a fatty meal or oral glucose, and in the rabbit, to injected insulin. HMW adiponectin was more rapidly metabolised than the trimeric form, but both were stable in vivo, and did not interconvert. We conclude that human adiponectin is much longer-lived than is the case with other hormones, a finding with positive implications for the potential to supplement levels of adiponectin in man.

Adiponectin↗
PubMed2002

Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans.

Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 +/- 8 years, body fat 29 +/- 8% [mean +/- SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). Group 1 (19 subjects) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR (stimulated by 100 nmol/l insulin). The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation. Group 2 (38 subjects) had follow-up measurements of insulin-stimulated glucose disposal. Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. In group 1 plasma adiponectin was negatively associated with the basal (r = -0.65, P = 0.003) and positively associated with the fold increase in IR tyrosine phosphorylation (r = 0.69, P = 0.001) before and after the adjustment for percent body fat (r = -0.58, P = 0.01 and r = 0.54, P = 0.02, respectively). Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P = 0.04). In conclusion, our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation. Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans.

Adiponectin↗
PubMed2006

Effect of adiponectin on murine colitis induced by dextran sulfate sodium.

BACKGROUND & AIMS: Adiponectin, an adipose tissue-derived hormone, exhibits anti-inflammatory properties and has various biological functions, such as increasing insulin sensitivity, reducing hypertension, and suppressing atherosclerosis, liver fibrosis, and tumor growth. The aim of the present study was to determine the effect of adiponectin on intestinal inflammation. METHODS: We investigated the effect of adiponectin on dextran sulfate sodium (DSS)-induced colitis by using adiponectin-knockout (APN-KO) mice and an adenovirus-mediated adiponectin expression system. We also examined the contribution of adiponectin deficiency to trinitrobenzene sulfonic acid (TNBS)-induced colitis. In vitro, we examined the effect of adiponectin on intestinal epithelial cells. RESULTS: After administration of 0.5% DSS for 15 days, APN-KO mice developed much more severe colitis compared with wild-type mice. The messenger RNA expression levels of chemokines were significantly higher in the colonic tissues of DSS-treated APN-KO mice compared with wild-type mice, accompanied by increased cellular infiltration, including macrophages. Adenovirus-mediated supplementation of adiponectin significantly attenuated the severity of colitis, but there were no differences in the severity of TNBS-induced colitis between the 2 groups. Adiponectin receptors were expressed in intestinal epithelial cells, and adiponectin inhibited lipopolysaccharide-induced interleukin-8 production in intestinal epithelial cells. CONCLUSIONS: Adiponectin is protective against DSS-induced murine colitis, probably due to the inhibition of chemokine production in intestinal epithelial cells and the following inflammatory responses, including infiltration of macrophages and release of proinflammatory cytokines.

Adiponectin↗
PubMed2007

Antiproliferative effect of adiponectin on MCF7 breast cancer cells: a potential hormonal link between obesity and cancer.

Adiponectin, a hormone secreted by adipose tissue, circulates at high concentrations in human plasma. Paradoxically, plasma levels of adiponectin are approximately 50% lower in obese than in lean subjects. An association between low plasma levels of adiponectin and higher risk of developing breast and other cancers was recently reported. Obesity and overweight have also been associated with increased mortality from cancer. To test the hypothesis that adiponectin exerts direct antiproliferative and/or pro-apoptotic effects on cancer cells, we used the MCF7 human breast adenocarcinoma cell line. The proliferation rate of the MCF7 cells was measured using the MTT method, while apoptosis was examined by quantifying the DNA fragmentation using an ELISA assay. In addition, adiponectin receptor 1 (AdipoR1) and AdipoR2 mRNA expression was detected using RT-PCR. Adiponectin diminished the proliferation rate of MCF7 cells; this effect was significant after 48-96 hours of treatment. The presence of receptor expression suggested that the effect of adiponectin on cell proliferation was most likely specific and adiponectin receptor-mediated. Adiponectin induced no apoptosis of MCF7 cells over 48 hours. We conclude that adiponectin inhibits proliferation but causes no apoptosis of MCF7 breast cancer cells. These data suggest that adiponectin may represent a direct hormonal link between obesity and cancer.

Adenocarcinoma↗
PubMed2006

Regulation of pituitary cell function by adiponectin.

Adiponectin is a member of the family of adipose tissue-related hormones known as adipokines, which exerts antidiabetic, antiatherogenic, antiinflammatory, and antiangiogenic properties. Adiponectin actions are primarily mediated through binding to two receptors expressed in several tissues, AdipoR1 and AdipoR2. Likewise, adiponectin expression has been detected in adipocytes as well as in a variety of extra-adipose tissues, including the chicken pituitary. Interestingly, adiponectin secretion and adiponectin receptor expression in adipocytes have been shown to be regulated by pituitary hormones. These observations led us to investigate whether adiponectin, like the adipokine leptin, regulates pituitary hormone production. Specifically, we focused our analysis on somatotrophs and gonadotrophs because of the relationship between the control of energy metabolism, growth and reproduction. To this end, the effects of adiponectin on both GH and LH secretion as well as its interaction with major stimulatory regulators of somatotrophs (ghrelin and GHRH) and gonadotrophs (GnRH) and with their corresponding receptors (GHS-R, GHRH-R, and GnRH-R), were evaluated in rat pituitary cell cultures. Results show that adiponectin inhibits GH and LH release as well as both ghrelin-induced GH release and GnRH-stimulated LH secretion in short-term (4 h) treated cell cultures, wherein the adipokine also increases GHRH-R and GHS-R mRNA content while decreasing that of GnRH-R. Additionally, we demonstrate that the pituitary expresses both adiponectin and adiponectin receptors under the regulation of the adipokine. In sum, our data indicate that adiponectin, either locally produced or from other sources, may play a neuroendocrine role in the control of both somatotrophs and gonadotrophs.

Adiponectin↗
PubMed2005

Expression of adiponectin and its receptors in swine.

Adiponectin is an adipocyte-derived hormone that plays an important role in lipid metabolism and glucose homeostasis. Objectives of this study were 1) to determine the presence and distribution of adiponectin and its receptors 1 and 2 (adipoR1 and adipoR2) in porcine tissues; 2) to characterize pig adiponectin, adipoR1, and adipoR2 mRNA levels in various fat depots from three different breeds of pigs; and 3) to study, in stromal-vascular cell culture, the effects of leptin and tumor necrosis factor-alpha (TNFalpha) on pig adiponectin, adipoR1, and adipoR2 gene expression. To this end, fat Chinese Upton Meishan (UM, n = 10), lean Ham Line (HL, n = 10), and Large White (LW, n = 10) gilts were used. We report the isolation of partial cDNA sequences of pig adipoR1 and adipoR2. Porcine-deduced AA sequences share 97 to 100% homology with human and murine sequences. Pig adipoR1 mRNA is abundant in skeletal muscle, visceral fat, and s.c. fat tissues, whereas adipoR2 mRNA is predominantly expressed in liver, heart, skeletal muscle, and visceral and s.c. fat tissues. Pig adiponectin mRNA levels in s.c. and visceral fat tissues were not associated with plasma insulin and glucose in fasting animals. Subcutaneous (r = -0.44, P < 0.05), visceral (r = -0.43, P < 0.05), and total body fat (r = -0.42, P < 0.05) weights were negatively correlated with adiponectin mRNA levels measured in visceral, but not s.c., fat. Pig adipoR1 and adipoR2 mRNA levels, in visceral fat, were less expressed in fat UM gilts than in the lean HL gilts (P < 0.05). Inverse associations were found between s.c. (r = -0.57, P < 0.01), visceral (r = -0.46, P < 0.05), and total body fat (r = -0.56, P < 0.01) weights and adipoR2 mRNA levels in visceral fat only. We were unable to find such associations for adipoR1 mRNA levels in the overall gilt population. The current study demonstrated that TNFalpha downregulates adiponectin and adipoR2, but not adi-poR1, mRNA levels in stromal-vascular cell culture. Moreover, leptin significantly decreased adiponectin mRNA levels, whereas there was no effect on adiponectin receptors. We conclude that adiponectin and adi-poR2 mRNA levels, but not adipoR1, are modulated in pig visceral fat tissues. Furthermore, our results indicate that TNFalpha interferes with adiponectin function by downregulation of adipoR2 but not of adipoR1 mRNA levels in pigs.

Adiponectin↗
PubMed2003

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex.

AIMS/HYPOTHESIS: Increased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins. METHODS: We measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S(I)) in 182 subjects (76 M/106F). RESULTS: Adiponectin concentrations were higher in women than in men (7.4+/-2.9 vs 5.4+/-2.3 micro g/ml, p<0.0001) as were leptin concentrations (19.1+/-13.7 vs 6.9+/-5.1 ng/ml, p<0.0001). Women were more insulin sensitive (S(I): 6.8+/-3.9 vs 5.9+/-4.4 x 10(-5) min(-1)/(pmol/l), p<0.01) and had more subcutaneous (240+/-133 vs 187+/-90 cm(2), p<0.01), but less intra-abdominal fat (82+/-57 vs 124+/-68 cm(2), p<0.0001). By simple regression, adiponectin was positively correlated with age ( r=0.227, p<0.01) and S(I) ( r=0.375, p<0.0001), and negatively correlated with BMI ( r=-0.333, p<0.0001), subcutaneous ( r=-0.168, p<0.05) and intra-abdominal fat ( r=-0.35, p<0.0001). Adiponectin was negatively correlated with triglycerides ( r=-0.281, p<0.001) and positively correlated with HDL cholesterol ( r=0.605, p<0.0001) and Rf, a measure of LDL particle buoyancy ( r=0.474, p<0.0001). By multiple regression analysis, adiponectin was related to age ( p<0.0001), sex ( p<0.005) and intra-abdominal fat ( p<0.01). S(I) was related to intra-abdominal fat ( p<0.0001) and adiponectin ( p<0.0005). Both intra-abdominal fat and adiponectin contributed independently to triglycerides, HDL cholesterol and Rf. CONCLUSION/INTERPRETATION: These data suggest that adiponectin concentrations are determined by intra-abdominal fat mass, with additional independent effects of age and sex. Adiponectin could link intra-abdominal fat with insulin resistance and an atherogenic lipoprotein profile.

Abdominal Wall↗
PubMed2005

The role of total and high-molecular-weight complex of adiponectin in vascular function in offspring whose parents both had type 2 diabetes.

AIMS/HYPOTHESIS: Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic properties. We studied the role played by total adiponectin and by the bioactive high-molecular-weight (HMW) oligomeric complexes of adiponectin in vascular function in offspring whose parents both had type 2 diabetes, a population at high risk of diabetes and atherosclerosis. METHODS: Total and %HMW adiponectin, the cytokines C-reactive protein, interleukin-6 and plasminogen activator inhibitor-1 (PAI-1), as well as lipid profiles were assayed in 19 offspring, each with two type 2 diabetic parents. Subjects underwent OGTTs and IVGTTs. Endothelium-dependent vasodilation (EDV) was assessed by brachial artery ultrasonography. RESULTS: There was a significant relationship between %HMW and total adiponectin levels (r=0.72, p=0.001). Despite an expected strong positive correlation between HDL-cholesterol and adiponectin levels (r=0.52, p=0.04), as well as HDL-cholesterol and EDV (r=0.56, p<0.02), there was no significant relationship between either total adiponectin or % HMW adiponectin and EDV. Adiponectin was inversely associated with PAI-1 (r=0.50, p=0.05), but did not correlate with the inflammatory markers C-reactive protein or interleukin-6. CONCLUSIONS/INTERPRETATION: In offspring of diabetic parents, a population at high risk of diabetes and atherosclerotic disease, there is no relationship between total or %HMW adiponectin and endothelium-dependent vasodilation. However, low adiponectin was associated with impaired fibrinolysis as manifested by increased levels of plasminogen activator inhibitor-1.

Adiponectin↗
PubMed2004

Urinary adiponectin excretion is increased in patients with overt diabetic nephropathy.

Adiponectin, a novel adipose-derived adipocytokine, has beneficial effects not only on improvement of insulin sensitivity but also on mitigation of vascular damage. To evaluate whether adiponectin is implicated in the pathogenesis of diabetic nephropathy characterized by microvascular damage, we examined urinary and serum adiponectin levels in type 2 diabetic patients with different stages of nephropathy. We first confirmed adiponectin is excreted into urine through Western blot analysis, followed by measurements of urinary and serum adiponectin levels by radioimmunoassay. Interestingly, urinary adiponectin excretion levels were markedly increased in patient group with overt nephropathy relative to the groups without nephropathy and with incipient nephropathy. Surprisingly, serum adiponectin levels were also elevated in patient group with overt nephropathy. Increased urinary adiponectin excretion may result from elevations in circulating adiponectin levels and enhanced filtration of circulating adiponectin through the damaged kidney. Furthermore, adiponectin synthesis in adipose tissue and its secretion into circulating blood may be enhanced to mitigate microvascular damage in the advanced stage of diabetic nephropathy.

Adiponectin↗
PubMed2005

Adiponectin as a growth inhibitor in prostate cancer cells.

Prostate cancer is associated with obesity. However, the molecular basis of this association is not well known. Adiponectin is a major adipose cytokine that decreases in circulation in obesity and ameliorates obesity. Here, we identify adiponectin as a novel inhibitor in prostate cancer cell growth. Adiponectin occurs in non-proteolytic (full-length adiponectin: f-adiponectin) and proteolytic (globular adiponectin) forms in various oligomeric states (trimer, hexamer, and high molecular weight complex). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay demonstrates that f-adiponectin inhibits prostate cancer cell growth drastically at subphysiological concentrations. Furthermore, velocity sedimentation analysis shows that the high molecular weight complex of f-adiponectin is the inhibitory form. Moreover, f-adiponectin suppresses leptin- and/or insulin-like growth factor-I (IGF-I)-stimulated, androgen-independent DU145 cell growth, and dihydrotestosterone-stimulated, androgen-dependent LNCaP-FGC cell growth. In addition, f-adiponectin enhances doxorubicin inhibition of prostate cancer cell growth. Therefore, f-adiponectin is a molecular mediator between prostate cancer and obesity, and may be therapeutic to prostate cancer.

Adipocytes↗
PubMed2006

A novel ELISA system for selective measurement of human adiponectin multimers by using proteases.

BACKGROUND: Adiponectin, an antiatherogenic adipocyte-derived protein exists in human blood as multiple isoforms--trimeric low molecular weight (LMW), albumin-binding LMW (Alb-LMW), hexameric middle molecular weight (MMW), and high molecular weight (HMW) forms. We developed a novel ELISA system to detect total human adiponectin and the selective level of each adiponectin multimer for investigating the distribution of these levels in human blood. METHODS: Two monoclonal antibodies that were raised against human adiponectin were used to construct a sandwich ELISA to measure adiponectin levels. Adiponectin multimers were selectively measured after sample pretreatment with two proteases that specifically digested the trimeric forms or both the hexameric and trimeric forms. RESULTS: The ELISA had a dynamic range of 0.075-4.8 ng/ml. Intraassay variations (CV) were 5.3% (total adiponectin), 4.1% (MMW+HMW), and 3.3% (HMW). Comparison of the results of ELISA and quantitative western blot analysis of multimeric adiponectin in serum samples revealed good correlation (LMW+Alb-LMW, r=0.873; MMW, r=0.907; HMW, r=0.950). Each of the three forms of adiponectin multimer levels closely correlated with total adiponectin levels in healthy subjects. CONCLUSIONS: This ELISA system can be used to further investigate the physiological roles of human adiponectin multimers.

Adiponectin↗