Triphenyl phosphate causes a sexually dimorphic metabolism dysfunction associated with disordered adiponectin receptors in pubertal mice.

The potential for triphenyl phosphate (TPhP) caused metabolic dysfunction has been documented. However, the relative mechanism of sexual dimorphic disruption on metabolism induced by TPhP remains unclear. Herein, we observed the insulin-sensitizing hormone (adiponectin) was inhibited in female serum while stimulated in males after oral administration of TPhP. Correspondingly, we found a high index of HOMA-IR in females. The primary receptors of adiponectin (AdipoR1 and AdipoR2) and the downstream: phosphorylation of AKT (pAKT) and PPAR⍺ signaling was attenuated in female liver. The disordered adiponectin/AdipoR signaling reduced hepatic glucose glycolysis and induced gluconeogenesis and finally led to the glucose intolerance in females. Also, the aberrant fatty acid ß-oxidation and hepatic triacylglyceride (TG) deposition were found in female liver. Comparably, TPhP upregulated the AdipoR 1/2 and induced the downstream (pAMPK and PPAR⍺ signaling) in males. Thus, the serum glucose and hepatic TG level remained normal. However, modulation on AdipoR1/R2 and the genes related to glucose and lipid disposal in skeletal muscle has no gender-specific effect. Our research firstly revealed TPhP-induced hepatic nutrient metabolism was partially mediated by the adiponectin/AdipoR pathway in sexual-dependent manner during pubertal.

Increasing Adiponergic System Activity as a Potential Treatment for Depressive Disorders.

Depression is the most devastating mental disorder and one of the leading contributors to the global medical burden. Current antidepressant prescriptions present drawbacks, including treatment resistance, delayed onset of treatment response, and side effects. The rapid and long-lasting antidepressant effect of ketamine has brought hope to treatment-resistant major depressive disorder patients. However, ketamine has undesirable addictive properties and is a drug of abuse. There is an urgent need, therefore, to develop novel pharmacological interventions that could be as effective as ketamine, but without its side effects. Adiponectin, a pleiotropic adipocyte-secreted hormone, has insulin-sensitizing and neurotrophic properties. It can cross the blood-brain barrier and target multiple brain regions where the adiponectin receptors are detected. Emerging evidence has suggested that adiponectin and the adiponectin receptor agonist, AdipoRon, could promote adult neurogenesis, dendritic and spine remodeling, and synaptic plasticity in the hippocampus, resulting in antidepressant effects in adult mice. By summarizing the most recent clinical and animal studies, this review provides a timely insight on how modulating the adiponergic system in the hippocampus could be a potential therapeutic target for an effective and fast-acting antidepressant response.

Role of Adiponectin in prostate cancer

ABSTRACT Obesity is defined as a chronic and excessive growth of adipose tissue. It has been associated with a high risk for development and progression of obesity-associated malignancies, while adipokines may mediate this association. Adiponectin is an adipose tissue-derived adipokines, with significant anti-diabetic, anti-inflammatory, anti-atherosclerotic and anti-proliferative properties. Plasma adiponectin levels are decreased in obese individuals, and this feature is closely correlated with development of several metabolic, immunological and neoplastic diseases. Recent studies have shown that prostate cancer patients have lower serum adiponectin levels and decreased expression of adiponectin receptors in tumor tissues, which suggests plasma adiponectin level is a risk factor for prostate cancer. Furthermore, exogenous adiponectin has exhibited therapeutic potential in animal models. In this review, we focus on the potential role of adiponectin and the underlying mechanism of adiponectin in the development and progression of prostate cancer. Exploring the signaling pathways linking adiponectin with tumorigenesis might provide a potential target for therapy.

The Effects of Adiponectin and Adiponectin Receptor 1 Levels on Macrovascular Complications Among Patients with Type 2 Diabetes Mellitus.

BACKGROUND/AIMS: The present study aimed to investigate the serum levels of adiponectin (APN) and adiponectin receptor 1 (AdipoR1) in patients with type 2 diabetes mellitus (T2DM) combined with macrovascular complications (MVC), as well as their correlation with clinical parameters. METHODS: A total of 60 T2DM patients were divided into 2 groups according to the presence of MVC: T2DM + MVC group (n=30) and T2DM group (n=30). Additionally, 30 healthy people were selected as control group (NC group). Clinical data and biological parameters were detected and recorded. T test was performed to compare the differences between two groups, and the results were corrected using Bonferroni method. Meanwhile, the correlation analysis and multiple stepwise regression analysis were used to analyze the association of APN and AdipoR1 with clinical factors. RESULTS: The levels of APN and AdipoR1 were significantly decreased in T2DM group and T2DM + MVC group compared with NC group, with the lowest value in T2DM + MVC group (all P<0.01). Serum APN levels were positively correlated with FINS and TG (r = 0.412, 0.316, respectively; both P<0.05), and negatively correlated with SBP, DBP and LDL-C (r = -0.292, -0.383, -0.334, respectively; all P<0.05). Serum levels of AdipoR1 were positively correlated with APN (r = 0.726, P<0.01), and negatively correlated with BMI, SBP, DBP, FBG, TC and LDL-C (r = -0.440, -0.446, -0.374, -0.444, -0.344, -0.709, respectively; all P<0.01). CONCLUSION: Serum levels of APN and AdipoR1 are significantly lower in T2DM group and T2DM + MVC group, showing lowest value in T2DM + MVC group. APN and AdipoR1 levels may influence glucose and lipid metabolism in T2DM patients.

Role of Adiponectin in prostate cancer.

Obesity is defined as a chronic and excessive growth of adipose tissue. It has been associated with a high risk for development and progression of obesity-associated malignancies, while adipokines may mediate this association. Adiponectin is an adipose tissue-derived adipokines, with significant anti-diabetic, anti-inflammatory, anti-atherosclerotic and anti-proliferative properties. Plasma adiponectin levels are decreased in obese individuals, and this feature is closely correlated with development of several metabolic, immunological and neoplastic diseases. Recent studies have shown that prostate cancer patients have lower serum adiponectin levels and decreased expression of adiponectin receptors in tumor tissues, which suggests plasma adiponectin level is a risk factor for prostate cancer. Furthermore, exogenous adiponectin has exhibited therapeutic potential in animal models. In this review, we focus on the potential role of adiponectin and the underlying mechanism of adiponectin in the development and progression of prostate cancer. Exploring the signaling pathways linking adiponectin with tumorigenesis might provide a potential target for therapy.

Endometrial gene expression in primiparous dairy cows at the end of the voluntary waiting period is affected by nutrition: Total mixed ration vs increasing levels of herbage allowance.

The study postulated that differential nutritional management during the early lactation period would be reflected in endometrial expression of genes related to embryo growth at the end of the voluntary waiting period. Thus, the effect of the combined use of total mixed ration (TMR) and grazing under different herbage allowances during the first 75 days post-partum (DPP) on endometrial gene expression was evaluated in primiparous dairy cows. Cows were blocked by body weight, age and body condition score and randomly assigned to three grazing treatments: high (HA, 30 kg DM per cow per day), medium (MA, 15 kg DM per cow per day) and low (LA, 7.5 kg DM per cow per day) herbage allowance (mixed pasture, 2,600 kg DM per ha) plus 8 kg DM of supplement or TMR (55% forage, 45% concentrate) fed ad libitum (TMR) from calving to 75 DPP. At 57 DPP, cows were synchronized for oestrus (day 0, 68 DPP) and at day 7, endometrial biopsies were obtained. The nutritional treatment did not affect insulin, IGF-1 and leptin concentrations on days 0, 4 or 7. Expression of IGF1, IGFBP3, IGFBP4, ADIPOR1 and ADIPOR2 mRNA was significantly affected by the nutritional treatment. Endometrial IGF1 and IGFBP4 mRNA were twofold greater in TMR and HA than MA and LA cows. Expression of IGFBP3 and ADIPOR1 mRNAs was greater in TMR and HA than MA cows, but did not differ from LA cows. All groups had greater expression of ADIPOR2 mRNA than MA cows. This study provided solid evidence of the importance of nutritional management during early lactation on uterine environment at the end of the voluntary waiting period. The greater expression of genes related to embryo growth and uterine function (IGF system, progesterone and adiponectin receptors) in cows fed diets maximizing energy intake suggests a favourable environment for embryonic growth, which may explain the improved reproductive performance of cows in good energy balance.

The Effect of Selenium Supplementation on Glucose Homeostasis and the Expression of Genes Related to Glucose Metabolism.

The aim of the study was to evaluate the effect of selenium supplementation on the expression of genes associated with glucose metabolism in humans, in order to explain the unclear relationship between selenium and the risk of diabetes. For gene expression analysis we used archival samples of cDNA from 76 non-diabetic subjects supplemented with selenium in the previous study. The supplementation period was six weeks and the daily dose of selenium was 200 µg (as selenium yeast). Blood for mRNA isolation was collected at four time points: before supplementation, after two and four weeks of supplementation, and after four weeks of washout. The analysis included 15 genes encoding selected proteins involved in insulin signaling and glucose metabolism. In addition, HbA1c and fasting plasma glucose were measured at three and four time points, respectively. Selenium supplementation was associated with a significantly decreased level of HbA1c but not fasting plasma glucose (FPG) and significant down-regulation of seven genes: INSR, ADIPOR1, LDHA, PDHA, PDHB, MYC, and HIF1AN. These results suggest that selenium may affect glycemic control at different levels of regulation, linked to insulin signaling, glycolysis, and pyruvate metabolism. Further research is needed to investigate mechanisms of such transcriptional regulation and its potential implication in direct metabolic effects.

Downregulation of adiponectin system in granulosa cells and low levels of HMW adiponectin in PCOS.

PURPOSE: The purpose of the study was to investigate changes in adiponectin system expression in granulosa cells (GCs) and high molecular weight adiponectin levels in serum and follicular fluid (FF) of 40 women with polycystic ovary syndrome (PCOS) compared to those in 40 women with normal ovary function. METHODS: Adiponectin (Adipo), adiponectin receptor 1 (AdipoR1), and adiponectin receptor 2 (AdipoR2) messenger RNA (mRNA) expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). High molecular weight (HMW) adiponectin protein concentration was evaluated by ELISA method. Data were analyzed using Student's t test and one-way ANOVA in SPSS 21 software. At oocyte retrieval, FF was aspirated and GCs were obtained from a pooled collection of FF per each patient. RESULTS: PCR results showed expression of adiponectin, AdipoR1, AdipoR2, follicle-stimulating hormone receptor (FSHR), and luteinizing hormone receptor (LHR) in GCs. After controlling body mass index (BMI) values, qRT-PCR demonstrated a decreased expression of adiponectin system in GCs of PCOS patients compared to those in controls (p = 0.001). There was a strong positive correlation among AdipoR1 and AdipoR2 expression and also among FSH and LH receptor expression. (Both r = 0.8, p = 0.001). There were low levels of high molecular weight adiponectin in the serum of PCOS patients with controlled ovarian hyperstimulation (30.19 ± 4.3 ng/ml) compared to the controls (48.47 ± 5.9 ng/ml) and in the FF of PCOS patients with controlled ovarian hyperstimulation (7.86 ± 1.44 ng/ml) compared to the controls (14.22 ± 2.01 ng/ml; p = 0.02). CONCLUSIONS: Lower expression of adiponectin and its receptors in GCs might be an important manifestation in gonadotropin-stimulated PCOS patients which could influence the physiologic adiponectin roles such as interaction with insulin and LH in induction of GC gene expression.

Expression of Adiponectin Receptors on Peripheral Blood Leukocytes of Hypertensive Children Is Associated with the Severity of Hypertension.

The aim of the study was to find out whether peripheral blood leukocyte adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) protein expression patterns (flow cytometry) differ between the primary hypertension children (n = 57) and healthy controls (n = 19) and if their expression levels are related to selected clinical parameters. The group of 26 patients [AdipoR(-)] showed lower and the group of 31 patients [AdipoR(+)] showed higher AdipoRs protein expression than the control and each other (P < 0.01 for neutrophils, P < 0.05 for monocytes). The AdipoR(+) leukocytes expressed higher AdipoR1 mRNA levels (RT-PCR) than AdipoR(-) ones and controls (P = 0.022 and P = 0.007, resp.). Despite greater BMI, the AdipoR(-) patients had unchanged serum adiponectin levels. In contrast, AdipoR(+) patients had lower serum adiponectin concentrations than the AdipoR(-) ones and controls (P < 0.001). The AdipoR(+) patients had higher blood pressure (P = 0.042) and greater carotid intima-media thickness (P = 0.017) than the AdipoR(-) ones. The stage of hypertension was associated with increased neutrophil but not monocyte AdipoR1 density (AdipoR1 MFI) (P < 0.05). Severe ambulatory hypertension was presented more often in AdipoR(+) patients than in AdipoR(-) ones (51.6% versus 26.9%, resp.; P < 0.01). In conclusion, neutrophil AdipoRs upregulation was associated with early stages of vascular injury, hypertension severity, and low serum levels of adiponectin.

Are decreased AdipoR1 mRNA levels associated with adiponectin resistance in coronary artery disease patients?

The aim of the present study was to investigate if circulating adiponectin levels and the expression of AdipoR1 and AdipoR2 in peripheral blood mononuclear cells (PBMC) are altered in coronary artery disease (CAD) patients, with and without significant stenosis, compared to healthy patients. The present study included 69 patients with presenting symptoms of CAD (26 patients with significant stenosis and 43 patients without significant stenosis). The control group (CG) consisted of 33 healthy patients. Circulating adiponectin levels were measured by enzyme-linked immunosorbent assay, whereas AdipoR1 and AdipoR2 mRNA levels in PBMC were determined by real-time polymerase chain reaction. Adiponectin levels were significantly higher in patients with and without significant stenosis compared to the CG (P < 0.001 vs P = 0.006, respectively). Both patient groups had lower AdipoR1 levels compared to the CG (P < 0.001 vs P < 0.001, respectively). There were no significant differences in these parameters between the two patient groups. Adiponectin negatively correlated with body mass index, triglycerides, insulin and homeostasis model assessment of insulin resistance index (HOMA IR), and positively with high-denisty lipoprotein cholesterol in the CG. Glucose, insulin, and the HOMA IR index negatively correlated with adiponectin in patients. A positive correlation between adiponectin receptors was found in patients and the CG. Decreased AdipoR1 mRNA levels and increased circulating adiponectin in advanced stages of CAD, as well as in patients without significant stenosis, compared to the CG, implies that CAD could be related to 'adiponectin resistance'. Despite increased adiponectin, its protective effects could be diminished even in early stages of atherosclerosis.

Adiponectin inhibits VEGF-A in prostate cancer cells.

A role of adiponectin in tumorigenesis has recently been appreciated. Although plasma adiponectin levels in subjects with prostate cancer have been found to be significantly lower than in subjects with benign prostatic hyperplasia or in normal healthy controls, the underlying molecular mechanisms remain unknown. Here, we not only detected significant decreases in plasma adiponectin levels in prostate cancer patients, but also showed significant decreases in adiponectin receptor I (AdipoR1) levels in the resected prostate cancer specimen. Prostate cancer cell lines examined in the current study had all lower levels of adiponectin and AdipoR1, compared to normal healthy prostate tissue. Moreover, overexpression of adiponectin in prostate cancer cells decreased production of vascular endothelial growth factor A (VEGF-A), while adiponectin depletion increased VEGF-A. Furthermore, adiponectin seemed to activate AMPK/TSC2 to inhibit mTor-mediated activation of VEGF-A. Taken together, our data suggest that adiponectin may play an essential role in suppressing growth of prostate cancer cells through inhibition of VEGF-A-mediated cancer neovascularization.

Genetic variation in adipokine genes and associations with adiponectin and leptin concentrations in plasma and breast tissue.

BACKGROUND: Circulating adipokines may be associated with breast cancer risk. Genetic variants governing adipokines and adipokine receptors may also predict risk, but their effect on breast adipokine concentrations is unknown. METHODS: We conducted a cross-sectional analysis of functional SNPs in 5 adipokine genes [adiponectin, leptin (LEP), and their receptors] among 85 cancer-free women who were undergoing reduction mammoplasty. RESULTS: In multivariable-adjusted regression models, compared with the common GG genotype, the AA genotype of the LEP A19G SNP was associated with 27% lower plasma adiponectin [ratio, 0.73; 95% confidence interval (CI), 0.54-0.98] and leptin (ratio, 0.73; 95% CI, 0.55-0.96). Women with the AG genotype of LEP A19G had 39% lower breast leptin (ratio, 0.61; 95% CI, 0.39-0.97) compared with those with the GG genotype. No associations were observed for SNPs in the remaining genes. CONCLUSIONS: Genetic variation in LEP may alter endogenous adipokine concentrations in circulation and in breast tissues. IMPACT: These preliminary findings may support the hypothesis that genetic variation in adipokine genes modifies circulating adipokine concentrations and possibly leptin concentrations in local breast tissues, which may be associated with breast cancer risk.

Involvement of insulin resistance in the protective effect of metformin against alcoholic liver injury.

BACKGROUND: Alcoholic liver disease (ALD) continues to be a major cause of morbidity worldwide. The exact mechanisms for ALD pathogenesis are not fully understood. There is currently no known available drug for ALD. Previous studies have suggested that ethanol (EtOH)-induced hepatic insulin resistance, through the inhibition of adenosine monophosphate-activated protein kinase (AMPK) and the expression of adiponectin as well as downstream enzymes, contribute to the development of ALD. This study was to determine the effects of EtOH on AMPK activity as well as the protective effect of metformin. METHODS: Forty male Wistar rats weighing 200 ± 20 g were randomized into 4 groups (n = 10) as follows: A = control group-rats received rodent chow; B = control + metformin group-rats received metformin (200 mg/kg/d intragastrically [IG]) at 21:00; C = EtOH group-rats were gavaged with alcohol of gradually increasing concentrations (30 to 60%, 5 to 9 g/kg/d) twice a day (9:00 and 16:00); D = EtOH + metformin group-rats received the same amount of EtOH as the rats in group C, and in addition received metformin (200 mg/kg/d IG) at 21:00. After 16 weeks, blood and liver samples were collected for further study. RESULTS: Chronic EtOH consumption led to liver injury both histologically and biochemically accompanied by insulin resistance, reduced AMPK activity, and dysregulation of downstream enzymes. Decreased levels of circulating adiponectin and decreased expression of proliferator-activated receptor gamma coactivator-1α (PGC-1α) and peroxisome proliferator-activated receptors-α (PPAR-α) in the hepatic tissue were observed. Treatment with metformin attenuated the severity of liver injury, restored AMPK activity and normalized the expression of acetyl-CoA carboxylase and fatty acid synthase. In addition, metformin also increased the circulating adiponectin and liver adiponectin receptor 2 expression. Furthermore, PGC-1α and PPAR-α activities were also restored. CONCLUSIONS: EtOH exposure induces hepatic insulin resistance. Metformin improved insulin resistance and reversed liver injury through the activation of AMPK and normalized adiponectin signaling making metformin a promising drug for the treatment of ALD.

Bisphenol A regulation of testicular endocrine function in male rats is affected by diet.

There is concern that early-life exposure to bisphenol A (BPA) may alter developmental programming and predispose individuals to obesity and reproductive anomalies. The present study was designed to determine if a high fat diet at sexual maturation moderates testicular toxicity occasioned by exposure to BPA during reproductive development. Therefore, male rats were exposed to BPA by maternal gavage (0, 2.5 or 25 µg/kg body weight/day) from gestational day 12 to postnatal day 21. At weaning, control and BPA-exposed animals were placed on a regular normal fat diet (NFD) until 70 days of age when they were continued on the NFD or were maintained on a high fat diet (HFD) until euthanasia at 98 days. Adult male rats maintained on HFD were generally heavier than NFD animals due to greater energy intake but energy intake per unit body weight gain was similar in all animals. However, perinatal exposure to BPA decreased (P<0.05) serum adiponectin as well as adiponectin and AdipoR2 protein expression levels in Leydig cells. Importantly, the combination of BPA exposure and HFD consumption promoted lipid peroxidation evidenced by elevated serum thiobarbituric acid reactive substances and glutathione concentrations. These findings imply that interaction between BPA and HFD potentially causes testicular dysfunction to a greater degree than would be due to BPA exposure or HFD consumption. Given the relationship that exists between energy homeostasis and reproductive activity, additional studies are warranted to investigate the consequences of BPA-diet interactions on testicular function.

Role of adiponectin and its receptor in prediction of reproductive outcome of metformin treatment in patients with polycystic ovarian syndrome.

AIMS: The aim of this study was to examine the effect of metformin on serum adiponectin and adiponectin receptor-1 (AdipoR1) and evaluate their role in prediction of ovulation in patients with polycystic ovarian syndrome (PCOS). MATERIAL AND METHODS: The study cohort included 68 PCOS patients with clomiphene citrate resistance (group 1) and 28 healthy women as controls (group 2). Baseline serum adiponectin, AdipoR1, total testosterone (T), and homeostasis model of insulin resistance (HOMA-IR) were measured in all participants. Group 1 received metformin (1500 mg/day) for 6 months followed by second blood sampling. RESULTS: Group 1 had significantly lower baseline adiponectin and AdipoR1 (P = 0.001) compared to group 2. During treatment, metformin resulted in conception in 5/68 (7%), ovulation in 33/68 (48%) and regular cycles in 41/68 (60%) patients. Group 1 showed post-metformin higher adiponectin and AdipoR1 (P = 0.01) and lower HOMA-IR (P = 0.006) and T (P = 0.001) compared to pre-treatment levels. Post-metformin ovulatory patients had higher adiponectin and AdipoR1 and lower HOMA-IR and T compared to anovulatory patients. Multivariate regression analysis in group 1 showed that only T and HOMA-IR were significant independent factors for predicting ovulatory cycles during metformin treatment (P = 0.04 and P = 0.05, respectively). CONCLUSIONS: Metformin treatment enhances both adiponectin activity and insulin sensitivity, resulting in a less hyperandrogenic state in patients with PCOS. Serum adiponectin and AdipoR1 are poor predictors of ovulatory outcome during treatment.

Adiponectin oligomers as potential indicators of adipose tissue improvement in obese subjects.

OBJECTIVE: Adiponectin is an adipocytokine that exerts beneficial effects on obesity and related disorders by two receptors (ADIPORs). Adiponectin is produced as a monomer that circulates in serum as different oligomers. The oligomerization state and the tissue expression of adiponectin and ADIPORs are linked to its biological activities. In this study, the levels of total adiponectin and its oligomers were evaluated in relation to obesity and surgical weight loss. The expression of adiponectin and ADIPORs was analyzed in visceral and subcutaneous adipose tissues of obese patients. DESIGN AND METHODS: In 25 obese patients and 44 age- and sex-matched controls, the serum levels of adiponectin and its oligomers were measured and compared by ELISA, western blotting, and gel filtration. The expression of adiponectin and ADIPORs in both adipose tissues was evaluated by real-time quantitative PCR and western blotting. RESULTS: The amount of each adiponectin oligomer, including the monomer, increases after weight loss. The reduced circulating levels of adiponectin and its oligomers are not associated with the adipose tissue depot-specific expression of adiponectin and ADIPORs. CONCLUSIONS: Our results suggest that in patients, adiposity is associated with the serum concentrations of adiponectin and its oligomers but not with adipose tissue depot-specific expression of adiponectin and ADIPORs. In particular, the increase in adiponectin monomer levels could probably be related to the improvement of the whole-body energy metabolism then being involved in the improvement of adipose tissue function after weight loss. This work indicates the importance of assessing the whole adiponectin oligomeric profile as further potential indicators of adipose tissue functions in obesity.

A comprehensive investigation of variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/R2), and their association with serum adiponectin, type 2 diabetes, insulin resistance and the metabolic syndrome.

BACKGROUND: Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. METHODS: Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. RESULTS: Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134). CONCLUSIONS: Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.

Association of serum adipocytokines with insulin resistance and liver injury in patients with chronic hepatitis C genotype 4.

BACKGROUND: Hepatitis C virus (HCV) infection, especially genotypes 1 and 4, is associated with metabolic dysfunction. We investigated the potential role of adipocytokines in HCV-induced insulin resistance (IR) and modulating the progression of liver disease in patients with HCV-4. METHODS: Serum adiponectin, high molecular weight adiponectin, leptin, tumor necrosis factor-α, interluekin-6, homeostasis model for the assessment of insulin resistance, and M30 protein were measured in 147 HCV patients and 89 controls. Liver biopsies were evaluated for steatosis/inflammation/fibrosis, adiponectin mRNA/protein, AdipoR1/-R2 mRNA, and phosphoenolpyruvate carboxykinase gene expression, and adiponectin and CD95 immunoreactivity. RESULTS: CD95 immunoreactivity and adiponectin immunoreactivity were detected in all biopsies examined. Hepatic adiponectin immunostaining correlated positively with the intensity of hepatic CD95/Fas immunostaining (r=0.424; P=0.001). Hepatocyte CD95/Fas upregulation correlated with fibrosis, inflammation, and steatosis (r=0.52, P=0.0001; r=0.16, P=0.04; r=0.24, P=0.0001; respectively). Significant correlations of serum adiponectin, its receptors mRNA expression, hepatic adiponectin immunostaining, and mRNA transcription for phosphoenolpyruvate carboxykinase were identified with steatosis. A positive association between adiponectin and hepatic inflammation and fibrosis was identified. This correlation remained significant even after adjusting for age, sex, and body mass index. Among body mass index, age, and sex-matched HCV-negative controls, patients with HCV-4 have higher serum leptin, adiponectin, and high molecular weight adiponectin, and these changes are independently correlated with IR. CONCLUSIONS: Our findings in patients with HCV-4 show that adiponectin correlates with IR and with the different stages of liver injury. Steatosis upregulates hepatocyte CD95/Fas and thus increases apoptosis, which facilitates inflammation and fibrosis. These findings may provide potential clues for novel therapeutic intervention.

The insulin sensitizing effects of PPAR-γ agonist are associated to changes in adiponectin index and adiponectin receptors in Zucker fatty rats.

The adiponectin high molecular weight isoform (HMW-adp) and its relation with the other adiponectin isoforms (adiponectin index, S(A)), have been identified as essential for the adiponectin insulin sensitizing effects. The objective of this study is to gain further insight on the effect of the insulin sensitizing agents, PPAR-γ agonists, on the distribution of the adiponectin isoforms and the adiponectin receptors, adipoR1 and adipoR2 in an animal model of obesity and insulin resistance. To achieve the objective, Zucker fatty rats were treated with pioglitazone, rosiglitazone or placebo for six weeks. At the end of the treatment, total adiponectin, adiponectin isoforms and adiponectin receptors expression were measured. In order to see the possible relation with insulin sensitivity parameters, HOMA-IR, muscle insulin-stimulated glucose transport, muscle GLUT4 and plasma free fatty acids were also measured. The two glitazones improved insulin sensitivity and both muscle insulin-stimulated glucose transport and GLUT4 total content. Total plasma adiponectin and visceral fat HMW-adp were increased only by pioglitazone. On the other hand, both glitazones changed the distribution of adiponectin isoforms in plasma, leading to an increase in the S(A) of 21% by pioglitazone and 31% by rosiglitazone. Muscle adipoR1 expression was increased by both glitazones whereas liver adipoR2 expression was increased by rosiglitazone and tended to increase in the pioglitazone group. The insulin sensitizing action of glitazones is mediated, at least in part, by their effect on muscle insulin-stimulated glucose transport and by their direct influence on the adiponectin index and the adiponectin receptors expression.

Dynamic alteration of adiponectin/adiponectin receptor expression and its impact on myocardial ischemia/reperfusion in type 1 diabetic mice.

The present study determined the dynamic change of adiponectin (APN, a cardioprotective adipokine), its receptor expression, and their impact upon myocardial ischemia/reperfusion (MI/R) injury during type 1 diabetes mellitus (T1DM) progression, and involved underlying mechanisms. Diabetic state was induced in mice via multiple intraperitoneal injections of low-dose streptozotocin. The dynamic change of plasma APN concentration and cardiac APN receptor-1 and -2 (AdipoR1/2) expression were assessed immediately after diabetes onset (0 wk) and 1, 3, 5, and 7 wk thereafter. Indicators of MI/R injury (infarct size, apoptosis, and LDH release) were determined at 0, 1, and 7 wk of DM duration. The effect of APN on MI/R injury was determined in mice subjected to different diabetic durations. Plasma APN levels (total and HMW form) increased, whereas cardiac AdipoR1 expression decreased early after T1DM onset. With T1DM progression, APN levels were reduced and cardiac AdipoR1 expression increased. MI/R injury was exacerbated with T1DM progression in a time-dependent manner. Administration of globular APN (gAD) failed to attenuate MI/R injury in 1-wk T1DM mice, while an AMP-activated protein kinase (AMPK) activator (AICAR) reduced MI/R injury. However, administration of gAD (and AICAR) reduced infarct size and cardiomyocyte apoptosis in 7-wk T1DM mice. In conclusion, our results demonstrate a dynamic dysfunction of APN/AdipoR1 during T1DM progression. Reduced cardiac AdipoR1 expression and APN concentration may be responsible for increased I/R injury susceptibility at early and late T1DM stages, respectively. Interventions bolstering AdipoR1 expression during early T1DM stages and APN supplementation during advanced T1DM stages may potentially reduce the myocardial ischemic injury in diabetic patients.