Low serum levels of high-molecular weight adiponectin in Indo-Asian women during pregnancy: evidence of ethnic variation in adiponectin isoform distribution.
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Decreased high-molecular weight adiponectin-to-total adiponectin ratio in sera is associated with insulin resistance in Japanese metabolically obese, normal-weight men with normal glucose tolerance.
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Adiponectin↗
Strong inverse correlation between serum adiponectin level and heart rate-corrected QT interval in an apparently healthy population: a suggestion for a direct antiatherogenic effect of adiponectin.
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Adiponectin stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway.
UNLABELLED: Our study indicates that recombinant adiponectin induced RANKL and inhibited OPG expression in human osteoblasts through the AdipoR1/p38 MAPK pathway, and these responses contributed to the adiponectin-induced osteoclasts formation in the co-culture of osteoblast and peripheral blood monocytes systems. These findings showed that adiponectin increased osteoclast formation indirectly through stimulating RANKL and inhibiting OPG production in osteoblasts. It also suggests the pharmacological nature of recombinant adiponectin that indirectly induces osteoclasts formation. INTRODUCTION: Recently, adiponectin has emerged as an element in the regulation of bone metabolism, but the mechanism remains. This study was undertaken to investigate the action of adiponectin on osteoclastogenesis through revealing RANKL and osteoprotegerin (OPG) expression in osteoblasts and osteoclast formation. MATERIALS AND METHODS: Real-time quantitative PCR and ELISA were used to detect RANKL and OPG mRNA and protein expression in cultured human osteoblasts. The involved signal pathway was studied using mitogen-activated protein kinase (MAPK) inhibitor and adiponectin receptor 1 (AdipoR1) siRNA. The effects of recombinant adiponectin on osteoclasts formation also were examined in the co-culture systems of osteoblast and peripheral blood monocytes (PBMCs) systems or purified CD14 + PBMCs cultures. RESULTS: Our study showed that recombinant adiponectin induced RANKL and inhibited OPG mRNA expression in human osteoblasts in a dose- and time-dependent manner. Adiponectin also increased soluble RANKL and decreased OPG secretion in osteoblasts conditioned media. Suppression of AdipoR1 with siRNA abolished the adiponectin-regulated RANKL and OPG mRNA expression in osteoblasts. Furthermore, pretreatment of osteoblasts with the MAPK inhibitor SB203580 abolished adiponectin-regulated RANKL and OPG mRNA expression. Adiponectin induced osteoclast formation in the co-culture systems of osteoblast and PBMCs systems, and OPG entirely blocked this response. However, adiponectin had no direct effect on the differentiation of osteoclast precursor purified CD14 + PBMCs. CONCLUSIONS: These data indicate that recombinant adiponectin induced RANKL and inhibited OPG expression in human osteoblasts through the AdipoR1/p38 MAPK pathway, and these responses contributed to the adiponectin-induced osteoclast formation in the co-culture of osteoblast and PBMCs systems. These findings showed that adiponectin increased osteoclast formation indirectly through stimulating RANKL and inhibiting OPG production in osteoblasts. It suggests the pharmacological nature of recombinant adiponectin that indirectly induces osteoclasts formation.
Adiponectin↗
Inhibition of the phosphatidylinositol 3'-kinase signaling pathway leads to decreased insulin-stimulated adiponectin secretion from 3T3-L1 adipocytes.
Adiponectin is a protein secreted by adipocytes, which modulates insulin resistance and is thought to confer protection from atherosclerosis. Decreased circulating adiponectin is seen in states of insulin resistance, yet the cause of this decrease remains unclear. We investigated the role of insulin in adiponectin secretion and the effect of selective insulin resistance on insulin-stimulated adiponectin secretion by 3T3-L1 adipocytes. Inhibition of the phosphatidylinositol 3'-kinase (PI3K) insulin-signaling pathway was induced with wortmannin (WT) or with a kinase-inactive Akt adenoviral construct (Akt-KD), and inhibition of the mitogen-activated protein kinase pathway was induced with PD98059 or with a dominant-negative ras adenoviral construct (DNras). The PI3K pathway was activated with a constitutively active Akt adenoviral construct (Akt-myr). Adiponectin was measured by Western blot, and adiponectin messenger RNA (mRNA) levels were determined by real-time reverse transcription-polymerase chain reaction. Insulin treatment increased adiponectin secretion and decreased intracellular adiponectin. Treatment with 100 nmol/L insulin for 24 hours resulted in a 78% increase in secreted adiponectin (P < .05). Insulin had no effect on adiponectin mRNA. WT or Akt-KD, but not PD98059 or DNras, inhibited insulin-stimulated adiponectin secretion (P < .05). Activation of the PI3K pathway resulted in increased insulin-independent adiponectin secretion. Inhibition of the PI3K- or mitogen-activated protein kinase-dependent pathway decreased adiponectin mRNA by 50% (P < .01). We demonstrate a decrease in insulin-stimulated adiponectin secretion with selective inhibition of the PI3K pathway. These results suggest a mechanism for the observed decreased adiponectin levels associated with insulin resistance, when defects in the PI3K-dependent insulin-signaling pathway lead to decreased adiponectin production, inadequate adiponectin secretion, and therefore low circulating adiponectin levels.
3T3-L1 Cells↗
Adiponectin in peritoneal dialysis patients: a comparison with hemodialysis patients and subjects with normal renal function.
BACKGROUND: Adiponectin, a cytokine with anti-inflammatory properties that is secreted from adipose tissue, is associated with insulin resistance. Adiponectin has been shown to be a predictor of cardiovascular events in both the general population and patients undergoing hemodialysis (HD); however, its role in peritoneal dialysis (PD) analogues remains unclear. METHODS: Serum adiponectin levels, measured by means of enzyme-linked immunosorbent assay in subjects with normal renal function and patients undergoing HD or PD (28 subjects in each group), were analyzed to establish the relationship between adiponectin and lipid levels, as well as insulin resistance. In the second study, 104 PD patients were recruited to analyze the relationships between serum adiponectin level and residual renal and peritoneal function and C-reactive protein (CRP) level. Independent factors for serum adiponectin level were determined from multiple linear regression. RESULTS: No significant difference was shown comparing serum adiponectin levels of PD and HD patients; however, both were significantly greater than those of control subjects (P < 0.01). Negative associations were shown between adiponectin and triglyceride (TG; P < 0.01) and insulin levels (P < 0.05) and homeostatic model assessment of insulin resistance (P < 0.01) for the former 2 groups; however, a positive association was shown for high-density lipoprotein (HDL) level (P < 0.05). Neither HD nor PD removed adiponectin significantly, with levels for the PD group negatively associated with residual renal function (P < 0.01) and CRP level (P < 0.001). PD patients administered glucose-lowering agents had lower adiponectin levels; however, lipid-lowering agents and renin-angiotensin blockades did not appear to affect them. Independent determinants for serum adiponectin level in PD patients were TG, HDL, and CRP levels and body mass index, after adjustment for age, sex, PD therapy duration, and diabetes. Adiponectin levels were not associated with left ventricular mass or ejection fraction. As for HD patients, PD patients had high adiponectin levels; adiponectin was not removed effectively using either of the studied dialysis modalities. In addition to a significant relationship with the components of insulin resistance, adiponectin level was associated with CRP level in these patients. CONCLUSION: These results indicate that adiponectin level in PD patients may be a good indicator of cardiovascular disease risk.
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Genetic and environmental factors influencing fasting serum adiponectin in Hispanic children.
CONTEXT: Because of its antiinflammatory and insulin-sensitizing properties, adiponectin may play a role in the development of cardiovascular disease and type 2 diabetes. OBJECTIVES: The aims of these analyses were: 1) to estimate the heritability of fasting serum adiponectin; 2) to evaluate the effects of age, sex, and body composition on fasting serum adiponectin; 3) to test for associations between fasting serum adiponectin and diet, fitness, energy expenditure, and fat oxidation; and 4) to determine the relationships between fasting serum adiponectin, insulin and lipids, and blood pressure in Hispanic children. DESIGN: Genetic and environmental factors influencing fasting serum adiponectin were investigated in a cohort of children participating in the VIVA LA FAMILIA Study in 2000-2005. SETTING: This study was performed at the Children's Nutrition Research Center. PARTICIPANTS: The study participants were 805 Hispanic nonoverweight and overweight children, ages 4-19 yr. MAIN MEASURE: The main measure of the study was fasting serum adiponectin. RESULTS: The heritability of serum adiponectin was 0.93 +/- 0.10 (P = 2.4 x 10(-40)). Adiponectin differed by age (P = 0.001), sex (P = 0.04), and weight (P = 0.001) status. Adiponectin levels declined with age, in association with changes in sex hormones and growth factors. Adiponectin was not associated with macronutrient intake, fitness, 24-h energy expenditure, or fat oxidation. Controlling for age, sex, and percent fat mass, adiponectin was inversely associated with homeostasis model of insulin resistance, triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure (P = 0.001). Significant positive genetic correlations were detected between adiponectin and total cholesterol (rho(G) = 0.19), HDL-C (rho(G) = 0.32), low-density lipoprotein cholesterol (rho(G) = 0.24), and IGF-binding protein-1 (rho(G) = 0.39), and negative genetic correlations were detected between adiponectin and leptin (rho(G) = -0.30), TG (rho(G) = -0.21), TG/HDL-C (rho(G) = -0.33), and IGF-binding protein-3 (rho(G) = -0.32), indicating shared genetic components in their expression. CONCLUSION: The high heritability of adiponectin and pleiotropy seen between adiponectin and leptin, growth factors, and lipids may play a role in the pathogenesis of cardiovascular disease and type 2 diabetes in overweight Hispanic children.
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Adiponectin in patients with various stages of coronary heart disease - comparison of its concentration in coronary arteries and peripheral venous circulation.
UNLABELLED: Adiponectin is an adipocytes-produced protein and showing a number of antiatherogenic effects. Adiponectin seems to be extensively deposited in the intersticium of venous lesions of persons with myocardial infarction. It may exhibit antiatherogenic and reparative effects. A decreased adiponectin concentration may be a risk factor of the origin and complications of atherosclerosis. AIM OF THE STUDY: 1) Do the adiponectin concentrations in venous blood of persons with acute coronary syndrome (ACS) differ from those in persons with stress angina pectoris? 2) In these persons do adiponectin concentrations in venous blood differ from those in main coronary arteries? 3) Do adiponectin levels differ in the infarction and non-infarction arteries in persons with STEMI (ST Elevation Myocardial Infarct) and delay within 4 hours after the onset? 4) In persons with ACS does any correlation exist between venous adiponectin and common risk factors of cardiovascular complications? Adiponectin concentration was determined in samples of blood collected from the peripheral vein and during coronarography in various localizations in 4 groups of examined persons (I. - no signs of CAD, II. - stable stress angina pectoris, III. - ACS over 48 hours without elevations of ST segment, IV. - STEMI during first 4 hours after its origin and proved occlusion of coronary artery at coronarography). Coronary angiography, risk factors and anamnestic data were analyzed. The software Medcalc was used to perform statistical analysis. We examined 73 probands with signs of myocardial ischemia (mean age of 61.5 years, 64 % males), who were subjected to coronarography and 21 healthy volunteers. A mean delay (delay from the origin of complaints to the performed coronarography) was 3.1 +/- 0.5 hours in individuals in the group IV. In patients with ACS we found lower adiponectin concentrations in venous blood compared to healthy individuals and persons with stress AP, but changes were not statistically significant (I.: -5.9 +/- 2.7 ng/l, II.: -4.9 +/- 1.2 ng/l, III.: -5.2 +/- 4.1 ng/l, IV.: -4.6 +/- 2.7 ng/l); no differences were found also with BMI. No significant difference was recorded between the samples of venous blood and those of coronary arteries, nor between the infarction and the non-infarction arteries in the group IV. (5.2 +/- 2.6 ng/l vs. 4.8 +/- -2.7 ng/l). Significant negative correlations were observed between adiponectin concentrations and BMI (correlation coefficient -0.29), triacylglycerols (correlation coefficient -0.4), AOPP (correlation coefficient -0.39), and positive correlations with HDL (correlation coefficient 0.32). No correlation was recorded between adiponectin and CRP. Adiponectin concentrations in persons with ACS are lower than in healthy persons or patients with stable angina pectoris, but differences are not statistically significant. The absence of adiponectin differences between the infarction/non-infarction artery may support the hypothesis of adiponectin uptake in the ischemic lesion with subsequent decrease in blood adiponectin. On the contrary, adiponectin decrease may be a risk factor independent of the origin and development of ACS.
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Regulation of adiponectin expression in human adipocytes: effects of adiposity, glucocorticoids, and tumor necrosis factor alpha.
OBJECTIVE: Adiponectin mRNA expression in isolated subcutaneous and omental adipocytes was examined across a wide range of adiposity to determine whether adiponectin synthesis is impaired in these adipose tissue depots in obese humans. Tumor necrosis factor (TNF)alpha and dexamethasone were tested for inhibitory effects on adiponectin release from human adipocytes in vitro. RESEARCH METHODS AND PROCEDURES: Adipocytes were isolated by collagenase digestion of abdominal adipose tissue obtained from subjects undergoing surgical procedures or outpatient needle biopsy. Adiponectin and leptin mRNA were quantitated by real-time reverse transcriptase-polymerase chain reaction. Adiponectin and leptin secretion from isolated adipocytes treated with dexamethasone or TNFalpha were determined by radioimmunoassay. RESULTS: There was a significant negative correlation between adiponectin gene expression and BMI in subcutaneous adipocytes from 32 women (r = 0.420; p = 0.02). Adiponectin mRNA was also significantly correlated with serum adiponectin (r = 0.44; p = 0.03; n = 25). There was no correlation between adiponectin mRNA expression and BMI in omental adipocytes from 29 women. Leptin mRNA was significantly and positively correlated (r = 0.484; p = 0.01) with BMI in the same omental adipocyte mRNA preparations. In subcutaneous adipocytes from lean subjects, TNFalpha inhibited adiponectin release by 7.4 +/- 1.2% (n = 9, p < 0.05) but had no effect on adiponectin release from subcutaneous or omental adipocytes from obese subjects. Dexamethasone significantly inhibited adiponectin release with 24 hours of treatment. DISCUSSION: The data suggest that reduced adiponectin synthesis in subcutaneous adipocytes contributes to lower serum adiponectin levels in obesity and that glucocorticoids regulate adiponectin gene expression in human adipocytes. TNFalpha does not seem to directly inhibit adiponectin synthesis in human adipocytes.
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Effect of postmenopause and hormone replacement therapy on serum adiponectin levels.
Little is known about the effects of menopause and hormone replacement therapy (HRT) on adiponectin production. The objectives of the study were to compare levels of serum adiponectin in post- and premenopausal women, to test whether adiponectin levels are related to endogenous estradiol and sex hormone-binding globulin (SHBG) levels, to determine whether HRT influences serum adiponectin, and to investigate relationships of adiponectin levels with cardiovascular risk factors. One hundred four women matched for body mass index were enrolled in this study, and among them were 34 postmenopausal HRT nonusers, 34 postmenopausal HRT users, and 36 premenopausal healthy women with regular menstrual cycles. We evaluated waist circumference and waist-to-hip ratio (WHR) in each women. Serum was assayed for adiponectin, estradiol, SHBG, triglycerides (TGs), total cholesterol, high-density lipoprotein cholesterol, and fasting glucose levels. Post- and premenopausal women showed no significant differences in adiponectin and SHBG concentrations. There were no differences in serum adiponectin levels between postmenopusal HRT nonusers and users; however, SHBG concentrations were higher in HRT users. The simple linear regression analyses of all studied women indicated that serum adiponectin was negatively correlated with body mass index, waist circumference, WHR, and TG levels. Positive correlation was observed between adiponectin and high-density lipoprotein cholesterol as well as between adiponectin and SHBG levels. There were no relationships between adiponectin and estradiol levels in all studied women and among subgroups. Multiple regression analysis showed that WHR and TG were significant independent predictors of serum adiponectin. In conclusion, serum adiponectin levels are not influenced by menopausal status or serum estradiol levels. Exogenous estrogen treatment does not significantly affect serum adiponectin concentrations.
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Regulation of adiponectin and leptin gene expression in white and brown adipose tissues: influence of beta3-adrenergic agonists, retinoic acid, leptin and fasting.
Circulating adiponectin levels fall whereas leptin levels rise with obesity, suggesting that regulation of these two adipocyte-derived hormones may be simultaneously influenced by common obesity-related factors. We examined adiponectin mRNA levels in WAT and in some instances, brown adipose tissue (BAT) following fasting and refeeding, acute and chronic administration of a beta(3)-adrenergic agonist, acute treatment with retinoic acid (RA) and a glucocorticoid, and following chronic infusion of leptin and compared the expression of adiponectin to that of leptin in each circumstance. Serum concentrations of adiponectin were also reported for most of the treatments. Fasting diminished and refeeding reversed both adiponectin and leptin gene expression. Peripheral injection of the beta(3)-adrenergic agonist, CL316,243, suppressed both leptin and adiponectin expression in WAT. A small but significant reduction in adiponectin expression in BAT was also observed following this treatment. Although CL316,23 lowered serum leptin levels markedly, it did not affect serum adiponectin levels. A chronic 7-day infustion of CL316,243 resulted in an elevation of adiponectin expression in WAT and serum concentrations in contrast to suppressions in both mRNA and serum levels of leptin by a similar treatment as previously reported. Chronic administration of leptin did not alter adiponectin synthesis in WAT compared to controls, but prevented the reduction in adiponectin synthesis associated with pair feeding. Food restriction through pair feeding also diminished adiponectin expression in BAT. Collectively, although leptin and adiponectin are inversely correlated with obesity, leptin does not appear to participate directly in adiponectin synthesis. The short-term regulation of the two adipokine expression in WAT is somewhat similar, perhaps subjective to common control of energy balance. The long-term regulation of adiponectin expression in WAT appears to be the opposite of that of leptin and may be more sensitive to changes in adiposity or insulin sensitivity.
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Cold exposure suppresses serum adiponectin levels through sympathetic nerve activation in mice.
OBJECTIVE: Several lines of evidence suggest important roles for adiponectin in glucose and lipid metabolism and atherosclerosis. However, the mechanisms regulating serum adiponectin levels and adiponectin production are still not completely understood. Our aim was to determine whether adiponectin synthesis is physiologically regulated by the sympathetic nervous system (SNS). RESEARCH METHODS AND PROCEDURES: Mice were exposed to cold (4 degrees C) for 12 hours and for 24 hours with or without inhibition of noradrenaline synthesis or pan-beta adrenergic function, followed by measurement of serum adiponectin concentrations and levels of adiponectin and uncoupling protein (UCP) 1 expressions in various white adipose tissues (WATs). RESULTS: Cold exposure significantly reduced serum adiponectin concentrations without changing body weights or WAT sizes in either subcutaneous or intra-abdominal fat tissues. The serum adiponectin reduction was associated with a decrease in adiponectin mRNA expression in subcutaneous, epididymal, and mesenteric fat tissues. In these adipose tissues, UCP1 expression was markedly enhanced, suggesting SNS activation in these tissues. Administration of alpha-methyl-p-tyrosine or a combination of SR59230A and propranolol reversed the cold-exposure-induced decreases in serum adiponectin concentrations and adiponectin mRNA expression in these tissues. In contrast, in retroperitoneal fat, the effects of cold exposure on adiponectin and UCP1 expressions were strikingly weak but were not reversed by SNS inhibitors. DISCUSSION: SNS physiologically regulates serum adiponectin levels and adiponectin synthesis in WATs in vivo, although responsiveness to SNS stimulation differs markedly among WATs. Sympathetic activation might be involved in development of the metabolic syndrome by modulation of serum adiponectin concentrations.
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Intracellular trafficking and secretion of adiponectin is dependent on GGA-coated vesicles.
Adiponectin (Acrp30) is an insulin-sensitizing hormone produced and secreted exclusively by adipose tissue. Confocal fluorescent microscopy demonstrated the colocalization of adiponectin with the Golgi membrane markers p115, beta-COP, and the trans-Golgi network marker, syntaxin 6. Treatment of cells with brefeldin A redistributed adiponectin to the endoplasmic reticulum where it colocalized with the chaperone protein BIP and inhibited secretion of adiponectin demonstrating a requirement for a functional Golgi apparatus for adiponectin release. Confocal fluorescent microscopy also demonstrated a colocalization of endogenous adiponectin with that of expressed GGA1myc (Golgi-localizing gamma-adaptin ear homology ARF-binding protein) but with no significant overlap between adiponectin and the GGA2myc or GGA3myc isoforms. Consistent with confocal fluorescent microscopy, transmission electron microscopy demonstrated the colocalization of GGA1 with adiponectin. Although GGA1 did not directly interact with the adiponectin protein, the adiponectin enriched membrane compartments of adipocyte were precipitated by a GST-GGA1 cargo binding domain (VHS) fusion protein but not with a GST-GGA2 VHS or GST-GGA3 VHS fusion proteins. Moreover, co-expression of adiponectin with a GGA1 dominant-interfering mutant (GGA1-VHS GAT domain) resulted in a marked inhibition of adiponectin secretion in both 3T3L1 adipocytes and HEK293 cells, whereas no inhibition was detected with the truncated mutants GGA2-VHSGAT or GGA3-VHSGAT. Moreover, co-expression of wild type GGA1 with adiponectin enhanced secretion of adiponectin. Interestingly, leptin secretion was unaffected by neither the wild type form or GGA1 mutant. Taken together these data demonstrate that the trafficking of adiponectin through its secretory pathway is dependent on GGA-coated vesicles.
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Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome.
OBJECTIVE: The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women. PATIENTS AND MEASUREMENTS: Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls. RESULTS: Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = -0.516, P < 0.001), fasting insulin (r = -0.404, P < 0.001), homeostasis model sensitivity (HOMA %S) (r = -0.424, P < 0.001) and testosterone (r = -0.279, P < 0.01), but no correlation with androstenedione (r = -0.112, P = 0.325), 17-OH-progesterone (r =-0.031, P = 0.784) or the LH/FSH ratio (r =-0.033, P = 0.753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0.55; P < 0.001), BMI (r =-0.575; P < 0.001), waist-to-hip ratio (WHR) (r =-0.48; P = 0.001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA) [Dexa-fat (total) (r = -0.61; P < 0.001) and Dexa-fat (trunk) (r = -0.59; P < 0.001)] and with testosterone (r = -0.42; P = 0.001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOS per se did not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0.59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia. CONCLUSIONS: PCOS per se is not associated with decreased levels of plasma adiponectin. However, circulating adiponectin is independently associated with the degree of insulin resistance in PCOS women and may contribute to the development and/or maintenance of insulin resistance independent from adiposity.
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Possible relationship between adiponectin and renal tubular injury in diabetic nephropathy.
Adiponectin is an adipose-derived protein which has anti-inflammatory and anti-atherogenic properties in addition to insulin-sensitizing effects. To date, the role of adiponectin in the pathogenesis of diabetic nephropathy remains unclear. The aim of the present study was to explore the relationship between adiponectin and renal tubular injury in diabetic nephropathy. We determined serum and urinary adiponectin levels in type 2 diabetic patients with normoalbuminuria (n = 19), microalbuminuria (n = 18), and overt diabetic nephropathy (n = 16), and then analyzed the correlations between serum and urinary adiponectin, urinary N-acetylglucosaminidase (NAG) as a clinical marker of renal tubular injury, urinary monocyte chemoattractant protein-1 (MCP-1) as an inflammatory marker in renal tubulointerstitium, and clinical markers of renal disease. Notably, serum and urinary adiponectin levels were significantly increased in patients with overt diabetic nephropathy compared to those with normoalbuminuria and microalbuminuria. In univariate linear regression analysis, serum adiponectin levels were positively correlated with serum creatinine (r = 0.648, P<0.0001), urinary albumin (r = 0.583, P<0.0001), urinary NAG (r = 0.406, P<0.01), urinary MCP-1 (r = 0.514, P<0.0001), and urinary adiponectin (r = 0.691, P<0.0001) levels in all diabetic patients. Urinary adiponectin levels were also positively correlated with serum creatinine (r = 0.729, P<0.0001), urinary albumin (r = 0.799, P<0.0001), urinary NAG (r = 0.701, P<0.0001), and urinary MCP-1 (r = 0.801, P<0.0001) levels in all diabetic patients. Multiple linear regression analysis showed that serum creatinine and urinary adiponectin levels were independently associated with serum adiponectin levels (r(2) = 0.522), and that serum creatinine, urinary NAG, urinary MCP-1, and serum adiponectin levels were independent determinants of urinary adiponectin levels (r(2) = 0.851). These results collectively indicate that renal insufficiency and tubular injury possibly play a contributory role in increases in serum and urinary adiponectin levels in overt diabetic nephropathy. We presume that an increase in circulating adiponectin in overt diabetic nephropathy might be a physiological response to mitigate renal tubular injury and to prevent the further progression of diabetic nephropathy through its anti-inflammatory and anti-atherogenic effects.
Acetylglucosaminidase↗
Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression.
Adiponectin is a 29-kDa adipocyte protein that has been linked to the insulin resistance of obesity and lipodystrophy. To better understand the regulation of adiponectin expression, we measured plasma adiponectin and adipose tissue adiponectin mRNA levels in nondiabetic subjects with varying degrees of obesity and insulin resistance. Plasma adiponectin and adiponectin mRNA levels were highly correlated with each other (r = 0.80, P < 0.001), and obese subjects expressed significantly lower levels of adiponectin. However, a significant sex difference in adiponectin expression was observed, especially in relatively lean subjects. When men and women with a BMI <30 kg/m(2) were compared, women had a twofold higher percent body fat, yet their plasma adiponectin levels were 65% higher (8.6 +/- 1.1 and 14.2 +/- 1.6 micro g/ml in men and women, respectively; P < 0.02). Plasma adiponectin had a strong association with insulin sensitivity index (S(I)) (r = 0.67, P < 0.0001, n = 51) that was not affected by sex, but no relation with insulin secretion. To separate the effects of obesity (BMI) from S(I), subjects who were discordant for S(I) were matched for BMI, age, and sex. Using this approach, insulin-sensitive subjects demonstrated a twofold higher plasma level of adiponectin (5.6 +/- 0.6 and 11.2 +/- 1.1 micro g/ml in insulin-resistant and insulin-sensitive subjects, respectively; P < 0.0005). Adiponectin expression was not related to plasma levels of leptin or interleukin-6. However, there was a significant inverse correlation between plasma adiponectin and tumor necrosis factor (TNF)-alpha mRNA expression (r = -0.47, P < 0.005), and subjects with the highest levels of adiponectin mRNA expression secreted the lowest levels of TNF-alpha from their adipose tissue in vitro. Thus, adiponectin expression from adipose tissue is higher in lean subjects and women, and is associated with higher degrees of insulin sensitivity and lower TNF-alpha expression.
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[Adiponectin and insulin sensitivity].
BACKGROUND: Adiponectin is a fat tissue protein that plays a role in maintaining the homeostasis of glucose and lipids, along with counteracting a number of risk factors associated with atherosclerosis and obesity. In addition, adiponectin has an effect on insulin sensitivity. The aim of this work was to assess concentrations of adiponectin in predefined groups of individuals and to analyse the associations between adiponectin and other metabolic parameters. METHODS AND RESULTS: The studied population comprised four groups of individuals, A-D. A--healthy controls, B--patients with impaired lipid metabolism, C--the obese, and D--patients with metabolic syndrome. When comparing the levels of adiponectin in groups of patients with impaired lipid metabolism (B), the obese (C), and patients with metabolic syndrome (D) with healthy controls (A), no statistically significant difference was observed between groups B and C and healthy individuals. In contrast, statistically significant difference was found when concentrations of adiponectin in patients with metabolic syndrome (D) were compared to those in healthy controls. Individuals with metabolic syndrome had the lowest levels of adiponectin - 5.3 mg/1 (men) and 5.6 mg/1 (women). The correlation coefficient for the association between adiponectin and HDL was R=0.57, for adiponectin and triglycerides R=-0.46, for adiponectin and BMI R=-0.37, for adiponectin and glycemia R=-0.34, for adiponectin and insulinemia R=-0.39, and for adiponectin and the QUICKI index R=0.44. CONCLUSIONS: One possible method of the complex evaluation of the metabolic syndrome development and its metabolic consequences is the assessment of adiponectin levels. Low levels of adiponectin indicate the development of insulin resistance.
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Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways.
Since interaction between bone and lipid metabolism has been suggested, this study investigated the regulation of bone metabolism by adiponectin, a representative adipokine, by analyzing deficient and overexpressing transgenic mice. We initially confirmed that adiponectin and its receptors were expressed in osteoblastic and osteoclastic cells, indicating that adiponectin can act on bone not only through an endocrine pathway as a hormone secreted from fat tissue, but also through an autocrine/paracrine pathway. There was no abnormality in bone mass or turnover of adiponectin-deficient (Ad-/-) mice, possibly due to an equivalent balance of the two pathways. In the culture of bone marrow cells from the Ad-/- mice, osteogenesis was decreased compared to the wild-type (WT) cell culture, indicating a positive effect of endogenous adiponectin through the autocrine/paracrine pathway. To examine the endocrine action of adiponectin, we analyzed transgenic mice overexpressing adiponectin in the liver, and found no abnormality in the bone. Addition of recombinant adiponectin in cultured osteoprogenitor cells suppressed osteogenesis, suggesting that the direct action of circulating adiponectin was negative for bone formation. In the presence of insulin, however, this suppression was blunted, and adiponectin enhanced the insulin-induced phosphorylations of the main downstream molecule insulin receptor substrate-1 and Akt. These lines of results suggest three distinct adiponectin actions on bone formation: a positive action through the autocrine/paracrine pathway by locally produced adiponectin, a negative action through the direct pathway by circulating adiponectin, and a positive action through the indirect pathway by circulating adiponectin via enhancement of the insulin signaling.
Adiponectin↗