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PubMed2006

Expression of the adiponectin receptors AdipoR1 and AdipoR2 in lean rats and in obese Zucker rats.

The adiponectin receptors, AdipoR1 and AdipoR2, are thought to transmit the insulin-sensitizing effects of adiponectin, an adipokine secreted by adipocytes. Modifications of their expression in insulin-sensitive tissues (skeletal muscle, liver, and adipose tissue) could therefore play a role in the control of insulin sensitivity and the development of insulin resistance. Recent data in mice supported this possibility. We examined whether the expression of adiponectin receptors (messenger RNA [mRNA] concentrations) is controlled in vivo in rats (Wistar) by nutritional factors (high-fat [HF] vs high-carbohydrate diet, fasting vs fed state) and whether this expression is decreased in an experimental model of insulin resistance, the obese Zucker rat. In Wistar rats, neither an HF diet nor fasting modified the mRNA concentrations of AdipoR1 in muscle, liver, or adipose tissue; the only modification observed was a decrease (P < .05) in AdipoR2 mRNA level in the liver of rats fed with an HF diet. In obese Zucker rats compared with their lean controls, neither AdipoR1 nor AdipoR2 expression was modified in muscle. AdipoR2 expression was slightly decreased in adipose tissue, whereas the expression of both AdipoR1 and AdipoR2 was increased (P < .05) in the liver of obese Zucker rats. In conclusion, contrary to what was reported in mice, the expression of adiponectin receptors in rats is poorly responsive to changes in nutritional conditions and is not decreased in a model of insulin resistance. These results do not support an important role for the expression of AdipoR1 and AdipoR2 in the modulation of sensitivity to insulin.

Animals↗
PubMed2006

Higher levels of adiponectin in American than in Japanese men despite obesity.

Levels of adiponectin are inversely associated with obesity levels. We examined the levels of adiponectin in American (n = 98) and Japanese (n = 92) men aged 40 to 49 years. Contrary to our expectations, the American men had higher levels of adiponectin than the Japanese men (13.3 +/- 5.8 vs 7.3 +/- 4.2 (microg/mL) despite higher levels of obesity. Smaller areas of visceral adipose tissue in American than in Japanese men may have resulted in the higher levels of adiponectin.

Adiponectin↗
PubMed2006

Differential BBB interactions of three ingestive peptides: obestatin, ghrelin, and adiponectin.

Endogenous compounds, including ingestive peptides, can interact with the blood-brain barrier (BBB) in different ways. Here we used in vivo and in vitro techniques to examine the BBB permeation of the newly described satiety peptide obestatin. The fate of obestatin in blood and at the BBB was contrasted with that of adiponectin. By the sensitive multiple time-regression method, obestatin appeared to have an extremely fast influx rate to the brain whereas adiponectin did not cross the BBB. HPLC analysis, however, showed the obestatin result to be spurious, reflecting rapid degradation. Absence of BBB permeation by obestatin and adiponectin was in contrast to the saturable transport of human ghrelin reported previously. As a positive control, ghrelin showed saturable binding and endocytosis in RBE4 cerebral microvessel endothelial cells. By comparison, obestatin lacked specific binding and endocytosis, and the small amount internalized showed rapid intracellular degradation before the radioactivity was released by exocytosis. The differential interactions of obestatin, adiponectin, and ghrelin with the BBB illustrate their distinctive physiological interactions with the CNS.

Adiponectin↗
PubMed2006

Cardioprotection by adiponectin.

Obesity-related disorders are closely associated with the pathogenesis of cardiovascular disease. Adiponectin is a circulating adipose tissue-derived hormone that is down-regulated in obese individuals. Hypoadiponectinemia has been identified as an independent risk factor for type 2 diabetes, coronary artery disease, and hypertension, and experimental studies show that adiponectin plays a protective role in the development of insulin resistance, atherosclerosis, and inflammation. More recent findings have shown that adiponectin directly affects signaling in myocardial cells and exerts beneficial actions on the heart after pressure overload and ischemia-reperfusion injury. This review focuses on the role of adiponectin in the regulation of myocardial remodeling and acute cardiac injury.

Adiponectin↗
PubMed2003

Disturbed secretion of mutant adiponectin associated with the metabolic syndrome.

Adiponectin, an adipocyte-derived protein, consists of collagen-like fibrous and complement C1q-like globular domains, and circulates in human plasma in a multimeric form. The protein exhibits anti-diabetic and anti-atherogenic activities. However, adiponectin plasma concentrations are low in obese subjects, and hypoadiponectinemia is associated with the metabolic syndrome, which is a cluster of insulin resistance, type 2 diabetes mellitus, hypertension, and dyslipidemia. We have recently reported a missense mutation in the adiponectin gene, in which isoleucine at position 164 in the globular domain is substituted with threonine (I164T). Subjects with this mutation showed markedly low level of plasma adiponectin and clinical features of the metabolic syndrome. Here, we examined the molecular characteristics of the mutant protein associated with a genetic cause of hypoadiponectinemia. The current study revealed (1) the mutant protein showed an oligomerization state similar to the wild-type as determined by gel filtration chromatography and, (2) the mutant protein exhibited normal insulin-sensitizing activity, but (3) pulse-chase study showed abnormal secretion of the mutant protein from adipose tissues. Our results suggest that I164T mutation is associated with hypoadiponectinemia through disturbed secretion into plasma, which may contribute to the development of the metabolic syndrome.

Adiponectin↗
PubMed2006

Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies.

Adiponectin, a protein exclusively secreted by adipose tissue but present at low levels in obesity, is now widely recognised as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. In this review we explain how genetic findings have contributed to a better understanding of the physiological role of adiponectin in humans. The adiponectin-encoding gene, ADIPOQ (ACDC), is very polymorphic: many frequent exonic synonymous, intronic and promoter single-nucleotide polymorphisms (SNPs) have been identified, as well as a few rare exonic amino acid substitutions. Several of these variations additively contribute to the modulation of adiponectin level and function, and associate with insulin sensitivity, type 2 diabetes and vascular complications of obesity.

Adiponectin↗
PubMed2005

Effect of the interleukin-6 (-174) g/c promoter polymorphism on adiponectin and insulin sensitivity.

We investigated the relation among the interleukin (IL)-6 (-174) G/C promoter polymorphism, adipose tissue gene expression of IL6, circulating adiponectin, and systemic insulin sensitivity. Eighty-five Swedish male subjects who had participated in our previous prediabetic phenotype characterization study were genotyped for the IL6 (-174) G/C polymorphism. Subcutaneous adipose tissue gene expression of IL6 and adiponectin was measured in 44 subjects. The IL6 (-174) G allele carriers had higher fasting plasma insulin levels (C/C, 7.8 +/- 1.1; G/C, 9.0 +/- 0.6; G/G, 10.5 +/- 1.0 mU/L) and higher homeostasis model assessment for insulin resistance (C/C, 1.6 +/- 0.2; G/C, 1.9 +/- 0.1; G/G, 2.2 +/- 0.2) compared with subjects with the C/C genotype. The circulating adiponectin levels were lower in the G allele carriers (C/C, 7.93 +/- 0.45; G/C, 7.05 +/- 0.44; G/G, 7.02 +/- 0.46 microg/mL), whereas the IL-6 levels did not differ among the three genotypes. Adipose tissue IL6 gene expression was significantly higher in the G allele carriers compared with the subjects homozygous for the C allele (C/C, 0.29 +/- 0.15; G/C, 0.84 +/- 0.29; G/G, 0.62 +/- 0.35). Our results suggest that IL6 (-174) G/C polymorphism is associated with insulin resistance and increased adipose tissue IL6 gene expression, which can impair adiponectin production.

Adiponectin↗
PubMed2006

The promoter region of the adiponectin gene is a determinant in modulating insulin sensitivity in childhood obesity.

We investigated the association of the -11,391G>A, -11,377G>C, +45T>G, and +276G>T adiponectin single-nucleotide polymorphisms (SNPs) and expected haplotypes with the insulin resistance (IR) state in overweight/obese children; by using the haplotype background analysis, we also assessed the effect of each SNP independently. GG genotype at the -11,391 locus was associated with higher fasting insulin levels and homeostasis model assessment-IR index and lower adiponectin levels compared with GA + AA genotypes (p = 0.01, 0.002, and 0.03, respectively). Those heterozygous and homozygous for G allele at the -11,377 locus showed higher fasting glucose (p = 0.001 for both), fasting insulin (p = 0.001 for both), homeostasis model assessment-IR index (p < 0.001 for both), and triglyceride levels (p = 0.02 and 0.03, respectively) and lower adiponectin levels (p = 0.002 and 0.02, respectively) compared with C homozygotes. The +45G carriers showed higher fasting and 2-hour glucose levels (p = 0.01 for both) and lower adiponectin levels (p = 0.02) compared with non-carriers. Haplotype analysis suggested that, considering the same haplotypic background, each of the three polymorphisms exerted an independent effect on investigated parameters. The -11,391G>A, -11,377C>G, and +45T>G SNPs are associated with IR syndrome in overweight/obese children; they independently influence the investigated variables. The effect of +45T>G SNP seems to be marginal compared with the promoter SNPs. The GGT haplotype is associated with the highest degree of IR.

Adiponectin↗
PubMed2006

Left ventricular mass and +276 G/G single nucleotide polymorphism of the adiponectin gene in uncomplicated obesity.

The single nucleotide polymorphism at position 276 in the adiponectin gene (APM1/ACDC +276 G>T) and left ventricular mass (LVM) have been associated with increased cardiovascular risk. We sought to evaluate whether +276 G>T variants in the adiponectin gene are correlated with LVM in uncomplicated obese subjects. APM1/ACDC +276 G>T single nucleotide polymorphism, echocardiographic indexed LVM (LVM/body surface area and LVM/height(2.7)), insulin sensitivity by euglycemic clamp, and plasma adiponectin levels were analyzed in 62 obese subjects without complications (51 women and 11 men; mean age, 34.2 +/- 10.2 years; BMI, 38.6 +/- 9.1 kg/m2). Forty lean subjects formed the control group for LVM evaluation. We found 23 (37%) uncomplicated obese subjects with the APM1/ACDC +276 G/G genotype, 25 (40%) with the G/T genotype, and 14 (23%) with the T/T genotype. G/G uncomplicated obese subjects showed significant higher LVM/body surface area and LVM/height(2.7) (within the normal range in the majority of them) than uncomplicated obese subjects carrying the G/T and T/T genotypes (p < 0.01 and p < 0.05, respectively). This study showed that LVM is significantly higher in uncomplicated obese subjects carrying the G/G genotype at position 276 of the human adiponectin gene.

Adiponectin↗
PubMed2006

Relationship between a wide range of alcohol consumptions, components of the insulin-like growth factor system and adiponectin.

OBJECTIVE: To explore the relation between a wide range of alcohol consumptions and levels of the components of insulin-like growth factor system (IGFs) and adiponectin in humans. DESIGN: A cross-sectional study using controls from a case-control study on ovarian and endometrial cancer. SETTINGS: The study included women hospitalized between 1999 and 2002 in Pordenone, Italy. SUBJECTS: One hundred and eight cancer-free (controls) with a median age of 61 years (range 29-79 years), admitted for acute conditions unrelated to gynecologic, hormonal or metabolic disorders or diseases leading to dietary modifications. INTERVENTIONS: Levels of IGF-I (total and free), total IGF-II, IGF-binding protein 1 (IGFBP-1), IGFBP-3 and adiponectin were individually measured, and their distributions across strata of alcohol consumption were tested by the Kruskal-Wallis statistic. RESULTS: Median concentrations of total IGF-I were higher (P<0.01) in women reporting low (151 ng/ml) or no alcohol consumption (134 ng/ml) compared to drinkers of 12-23 g/day (103 ng/ml) or >or=24 g/day (118 ng/ml). Median concentrations were higher (P=0.05) for IGFBP-3 in non-drinkers (2333 ng/ml) and in light drinkers (2647 ng/ml) compared to drinkers of >or=24 g/day (2090 ng/ml). No statistically significant difference emerged for other IGFs across levels of alcohol intakes. Adiponectin was slightly lower for non-drinkers, compared to all drinkers categories. CONCLUSIONS: Our study suggests that alcohol consumption is related to circulating levels of components of the IGF system and adiponectin. These results may have a potential impact on the prevention of several chronic diseases. SPONSORSHIP: Italian Association for Research on Cancer, Milan, Italy, and Italian League against Tumours, Milan, Italy.

Adiponectin↗
PubMed2005

Lower-body fat mass as an independent marker of insulin sensitivity--the role of adiponectin.

AIMS: To study the association between lower-body fat and estimates of whole-body insulin sensitivity in middle-aged men with and without a history of juvenile onset obesity, and to determine the possible mediating role of fasting serum adiponectin level as an insulin-sensitizing peptide. METHODS: A total of 401 men aged 39-65 y, body mass index 18-54 kg/m2, participated in the study. The following variables were measured on the study participants: regional body fat distribution as assessed by dual energy X-ray absorptiometry, abdominal sagittal diameter, maximal oxygen uptake (VO2max), physical activity, fasting and post-glucose load levels of plasma glucose, serum insulin, and blood non-esterified fatty acid plus fasting levels of serum adiponectin and HbA1c. RESULTS: Lower-body fat mass was positively associated with insulin sensitivity as estimated by Matsudas index also after adjusting for age, lean tissue mass, trunkal fat mass, weight changes since draft board examination, VO2max and the level of physical activity. In a subgroup of men selected for a large lower-body fat mass, fasting serum insulin concentration was 24% lower (P<0.01) and fasting serum adiponectin 33% higher (P<0.005) compared to a subgroup of men with a small lower-body fat mass but with similar trunkal fat mass. CONCLUSION: Lower-body fat mass is positively associated with an estimate of insulin sensitivity independently of trunkal fat mass in both lean and obese middle-aged men and this effect could partly be statistically explained by variations in serum adiponectin levels.

Absorptiometry, Photon↗
PubMed2006

Effect of nifedipine on adiponectin in hypertensive patients with type 2 diabetes mellitus.

Nifedipine, a dihydropyridine calcium antagonist, improves endothelial function in patients with hypercholesterolaemia by enhancing nitric oxide (NO) activity, and increases endothelial NO bioavailability by antioxidant mechanisms. We administered a long-acting nifedipine formulation (controlled release (CR) nifedipine: 20 mg/day) to hypertensive patients for 6 months. There were no other changes of drug treatment during therapy with CR nifedipine. Clinical and biochemical data obtained before and after CR nifedipine administration were compared. All markers were measured by enzyme-linked immunosorbant assay. The levels of soluble markers (soluble CD40 ligand, soluble P-selectin, and soluble E-selectin), microparticles (MP) (platelet-derived MP, monocyte-derived MP, and endothelial cell-derived MP), and adiponectin differed between the control group and the hypertension group. The levels of these markers were also different in hypertensive patients with and without type 2 diabetes compared with the control group. In the hypertensive patients with type 2 diabetes, all markers except adiponectin decreased significantly after 3 months of CR nifedipine treatment. In contrast, markers were unchanged in the hypertensive patients without type 2 diabetes. Adiponectin was increased after 6 months of CR nifedipine treatment in hypertensive patients with type 2 diabetes. The effects of CR nifedipine on platelet/monocyte activation and adiponectin levels demonstrated in the present study indicate the potential effectiveness of calcium antagonist therapy for hypertensive patients with type 2 diabetes.

Adiponectin↗
PubMed2005

Leptin, adiponectin, and ghrelin dysregulation in chronic kidney disease.

In the past 10 years, 3 new metabolic compounds, leptin, adiponectin, and ghrelin, involved in energy metabolism, body composition, and appetite regulation, have been discovered. We have assessed their characteristics in 46 patients with stage 3 to 4 chronic kidney disease to evaluate the role of decreased renal function in the abnormal handling reported in more severe end-stage renal disease patients. In addition to the usual correlations with body mass index and body fat mass, the results show unexpected positive correlations between leptin and insulin, leptin and adiponectin, a weak inverse relationship between adiponectin and glomerular filtration rate, and no influence of C-reactive protein on either leptin or adiponectin in these noninflamed patients. Serum ghrelin was inversely correlated with body mass index and with glomerular filtration rate as measured by inulin clearance. Thus, ghrelin and leptin, 2 antagonist signals for energy balance, both seem to increase when glomerular filtration rate is reduced, potentially neutralizing their respective biologic effects in severe renal insufficiency.

Adiponectin↗
PubMed2002

Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes.

The aim of this study was to evaluate the effects of pioglitazone on clinical and metabolic parameters, body fat distribution, and serum adiponectin, a recently discovered antiatherosclerotic hormone, in Japanese patients with type 2 diabetes. Ten male patients aged 40 to 66 (57.7 +/- 7.4) years, who were being treated with dietary therapy alone (n = 7) or with a stable dose of sulfonylurea (n = 3), were studied at baseline and after 3 months of pioglitazone treatment (30 mg/d). Body mass index (BMI), blood pressure, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), serum insulin, adiponectin, and lipid profile were measured. Also, visceral adipose tissue area (VAT) and subcutaneous adipose tissue area (SAT) at the umbilical level were determined by computed tomographic (CT) scanning. Mean blood pressure (109 +/- 14 to 101 +/- 10 mm Hg), FPG (8.6 +/- 1.4 to 7.0 +/- 1.0 mmol/L), serum insulin (54 +/- 11 to 30 +/- 8 pmol/L, P <.01 for all), and HbA1c (6.7 +/- 0.8 to 6.1% +/- 0.6%, P =.013) decreased significantly during 3 months of pioglitazone treatment. BMI (26.4 +/- 3.2 to 27.0 +/- 3.5 kg/m2), low-density lipoprotein (LDL) cholesterol (124 +/- 24 to 138 +/- 24 mg/dL) and SAT (155 +/- 69 to 179 +/- 81cm2, P <.05 for all) increased, while triglycerides and high-density lipoprotein (HDL) cholesterol did not change significantly after 3 months of pioglitazone treatment. Serum adiponectin level increased in all patients (4.8 +/- 1.7 to 14.4 +/- 2.1 microg/mL, P =.005). VAT tended to increase (165 +/- 38 to 180 +/- 46 cm2) and VAT/SAT ratio tended to decrease (1.2 +/- 0.3 to 1.1 +/- 0.3), but these differences did not reach statistical significance. These results suggest that pioglitazone exerts good glycemic and blood pressure control despite increased BMI and SAT in Japanese male patients with type 2 diabetes. It is also suggested that pioglitazone may have an antiatherosclerotic effect by increasing serum adiponectin level.

Adiponectin↗
PubMedDate not supplied

Relationship between IL-6, leptin and adiponectin and variables of fibrinolysis in overweight and obese hypertensive patients.

Impaired fibrinolysis is a common finding in obese humans. This condition is now considered as an established risk factor for thromboembolic complications. Furthermore, obesity is characterized by a specific pattern of circulating concentrations of fat-cell products interleukin-6 (IL-6), leptin, and adiponectin. The aim of our study was to investigate the relationship between these proteins and selected variables of the fibrinolytic system in 74 mildly hypertensive, overweight subjects. Circulating IL-6 and leptin levels showed a positive association with BMI (r = 0.24, p = 0.04 and r = 0.70, p < 0.0001), whereas adiponectin was not correlated to BMI. Interestingly, IL-6 was also positively associated with t-PA/PAI-1 complexes after adjustment for BMI and other anthropometric variables. Leptin was positively correlated with PAI-1 activity and antigen (r = 0.32, p = 0.006 and r = 0.37, p < 0.001, respectively) and negatively with t-PA activity (r = -0.27, p = 0.03). However, these associations lost significance after correction for BMI or HOMA, an insulin sensitivity index. In contrast, adiponectin levels were independently and negatively correlated with PAI-1 antigen (r = -0.26, p = 0.04, after correction for BMI). In conclusion, our study provides further evidence that IL-6, leptin, and adiponectin are associated with impaired fibrinolysis in overweight hypertensive humans.

Adipocytes↗
PubMedDate not supplied

Effects of soy protein diet on the expression of adipose genes and plasma adiponectin.

Many studies have reported the cholesterol-lowering, anti-lipogenic, anti-obesity and anti-hypertensive effects of soy protein. Adipose tissue-specific plasma protein, adiponectin, has anti-atherogenic and anti-insulin-resistance properties. Here, we investigated the effects of soy protein diet on body fat composition, plasma glucose, lipid and adiponectin levels and expression of genes involved in glucose and fatty acid metabolism in obese KK-A y mice. Body weights and adipose tissue weights of mesenteric, epididymal, and brown fat were lower in mice on calorie-restricted diet containing soy protein isolate. Plasma cholesterol, triglyceride, free fatty acid, and glucose levels were also decreased by this diet. Body fat content and plasma glucose levels in mice on a soy protein isolate diet were still lower than those treated with an isocaloric casein-protein-diet. Among the genes related to glucose and fatty acid metabolism, adiponectin mRNA levels in adipose tissue and adiponectin plasma concentrations were elevated in mice on a calorie-restricted diet, although there were no significant differences between soy protein and casein protein groups. Our results indicate that that soy protein diet decreased body fat content and plasma glucose levels more effectively than isocaloric casein-protein diet in obese mice.

Adiponectin↗
PubMed2005

Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism.

Abnormal glucose tolerance is associated with subclinical chronic inflammation in patients with type 2 diabetes. The aim of this study was to investigate whether plasma concentrations of inflammatory markers are associated with measures of obesity, insulin sensitivity, and hyperglycemia. IL-6, adiponectin, CRP, and IL-10 plasma concentrations were evaluated in 142 patients with a wide range of obesity, insulin sensitivity and glucose tolerance. In parallel with the impairment of glucose tolerance, there was a significant increase in IL-6, and CRP, and a significant decrease in adiponectin and IL-10 plasma concentrations. There were significant correlations between the plasma concentrations of all inflammatory markers and % body fat, insulin sensitivity, and fasting plasma glucose. However, multivariate linear regression analysis identified insulin sensitivity as determined by glucose infusion rate during the steady state of an euglycemic-hyperinsulinemic clamp as the strongest predictor of adiponectin, CRP, IL-6, and IL-10 plasma concentrations. In addition, fasting plasma glucose was a significant determinant of adiponectin, CRP, and IL-6 plasma concentrations, whereas body fat content was only a significant predictor of CRP plasma concentration. In conclusion, our data suggest that abnormal inflammatory markers in patients with type 2 diabetes are primarily related to decreased insulin sensitivity.

Adiponectin↗
PubMed2005

Adiponectin polymorphisms, adiposity and insulin metabolism: HERITAGE family study and Oulu diabetic study.

AIMS/HYPOTHESIS: Adiponectin is an adipocytokine with lowered blood levels in obesity and Type 2 diabetes mellitus. We sought to define the specific effects of different alleles of the gene encoding adiponectin. METHODS: We studied the associations of adiponectin gene sequence variations with body fat distribution and insulin indices in 503 White and 276 Black subjects of the HERITAGE Family Study cohort and subjects from a Finnish population. RESULTS: The His111 allele frequency of the Tyr111 His polymorphism in Finnish Type 2 diabetic subjects (n=254) was higher (5.1%) than in control subjects (n=270) (2.6%; P = 0.033). In the HERITAGE cohort, the His111 allele was associated with a lower insulin sensitivity index (P = 0.018) and a higher acute insulin response to glucose (P = 0.0098) in Whites. Other variants showed associations with adiposity and plasma lipid values only in Blacks. Among Blacks, the IVS2+G62T variant was associated with body fat (P = 0.002) and total cholesterol values (P = 0.005), and the Gly15Gly variant with cholesterol (P = 0.009) and triglyceride (P = 0.05) levels. The haplotype derived from these two polymorphisms was associated with total body fat, while the IVS2+G62T and Tyr111His-haplotype was associated with body fat and disposition index. CONCLUSIONS: The carriers of the His111 allele may have a higher risk of developing Type 2 diabetes mellitus. Racial differences were found between Blacks and Whites in body composition and lipids according to ACDC genotypes. Sequence variants in the adiponectin gene appear to be associated with diabetes and diabetes-related phenotypes.

Adipocytes↗