Correlation between plasma ZAG and adiponectin in older adults: gender modification and frailty specificity

Background Adiponectin and zinc alpha2-glycoprotein (ZAG) are associated with frailty. This study aims to further examine the association of adiponectin with ZAG. Methods Outpatients aged 65 years or older with chronic disease followed up in a hospital-based program were recruited for a comprehensive geriatric assessment. We excluded outpatients who were bedridden, residing in a nursing home, with expected life expectancy less than 6 months, or with severe hearing or communication impairment. Plasma ZAG and adiponectin levels were measured. Association between plasma ZAG and adiponectin levels was analyzed by univariate and multivariable linear regression analyses. Results A total of 189 older adults were enrolled (91 men and 98 women, mean age: 77.2 ± 6.1 years). Log-transformed plasma ZAG level was 1.82 ± 0.11 μg/mL, and it was significantly higher in men than that in women (1.85 ± 0.12 vs 1.79 ± 0.10 μg/mL, P = .0006). Log-transformed plasma adiponectin level was 1.00 ± 0.26 μg/mL, and there was no significant gender difference (P = .195). Overall, plasma ZAG level positively correlated with plasma adiponectin level in the multivariable linear regression analysis (P = .0085). The gender-specific significance, however, was less clear: this relationship was significant in men (P = .0049) but not in women (P = .2072). To be more specific by frailty phenotype components, plasma adiponectin was positively correlated with weight loss (P = .0454) and weakness (P = .0451). Conclusions Both of ZAG and adiponectin may be potential frailty biomarkers. Plasma ZAG is an independent factor of plasma adiponectin, especially in older male adults.

12α-Hydroxylated bile acid enhances accumulation of adiponectin and immunoglobulin A in the rat ileum

We previously reported that dietary supplementation with cholic acid (CA), the primary 12α-hydroxylated (12αOH) bile acid (BA), reduces plasma adiponectin concentration in rats. The aim of this study was to examine the distribution of adiponectin in the body of CA-fed rats and its influence on mucosal immunoglobulin A concentration in the intestine. Rats were fed a diet supplemented with or without CA (0.5 g CA/kg diet) for 13 weeks. A reduction in plasma adiponectin level was observed from week 3. At the end of the experiment, the CA diet reduced plasma adiponectin concentration both in the portal and aortic plasma. Accumulation of adiponectin was accompanied by an increase in cadherin-13 mRNA expression in the ileal mucosa of CA-fed rats. No increase was observed in adiponectin mRNA expression in the ileal and adipose tissues of the CA-fed rats. Immunoglobulin A concentration in the ileal mucosa was elevated in the CA-fed rats and was correlated with the ileal adiponectin concentration. 12αOH BAs may modulate mucosal immune response that are involved in the accumulation of adiponectin in the ileum.

Relationship between Plasma Adiponectin Level and Corrected QT interval in Smoker and Non-Smoker Adult Male Subjects

Objective. This study determined the relationship between plasma adiponectin level and corrected QT interval (QTc) in smokers and non-smokers. Methodology. This cross-sectional analytical study was undertaken in 30 smokers and 30 non-smokers. Plasma adiponectin level was determined by enzyme-linked immunosorbent assay (ELISA). The QT interval was measured by routine 12-lead ECG with Lead II rhythm and QTc was calculated. Results. Mean plasma adiponectin level was significantly lower in smokers (27.89±15 μg/ml) than that of non-smokers (52.13±21.57μg/ml) (p<0.001). Mean QTc interval was significantly longer in smokers than that of non-smokers (415.37±29.9 versus 395.63±26.13 ms, p<0.01). Higher risk of low adiponectin level (odds ratio [OR],8.1; 95% confidence interval [CI],1.61-40.77) and QTc interval prolongation (OR,6; 95%CI,1.17-30.73) were observed in smokers. There was weak significant negative correlation between plasma adiponectin level and QTc interval in the study population (n=60, r=-0.407, p=0.001). Moreover, low plasma adiponectin level was significantly associated with prolonged QTc interval in the study population (n=60, Fisher's exact p value<0.05). Risk of QTc interval prolongation was 4.3 times higher in subjects with low plasma adiponectin level (OR,4.27; 95% CI,1.05-17.46). Conclusion. Smokers have greater risk for low plasma adiponectin level and prolonged QTc interval. There is a relationship between plasma adiponectin level and QTc interval.

Multi-SNP mediation intersection-union test

Summary Tens of thousands of reproducibly identified GWAS (Genome-Wide Association Studies) variants, with the vast majority falling in non-coding regions resulting in no eventual protein products, call urgently for mechanistic interpretations. Although numerous methods exist, there are few, if any methods, for simultaneously testing the mediation effects of multiple correlated SNPs via some mediator (e.g. the expression of a gene in the neighborhood) on phenotypic outcome. We propose multi-SNP mediation intersection-union test (SMUT) to fill in this methodological gap. Our extensive simulations demonstrate the validity of SMUT as well as substantial, up to 92%, power gains over alternative methods. In addition, SMUT confirmed known mediators in a real dataset of Finns for plasma adiponectin level, which were missed by many alternative methods. We believe SMUT will become a useful tool to generate mechanistic hypotheses underlying GWAS variants, facilitating functional follow-up. Availability and implementation The R package SMUT is publicly available from CRAN at https://CRAN.R-project.org/package=SMUT. Supplementary information Supplementary data are available at Bioinformatics online.

Multi-SNP Mediation Intersection-Union Test

ABSTRACTTens of thousands of reproducibly identified GWAS (Genome-Wide Association Studies) variants, with the vast majority falling in non-coding regions resulting in no eventual protein products, call urgently for mechanistic interpretations. Although numerous methods exist, there are few, if any methods, for simultaneously testing the mediation effects of multiple correlated SNPs via some mediator (for example, the expression of a gene in the neighborhood) on phenotypic outcome. We propose SMUT, multi-SNP Mediation intersection-Union Test to fill in this methodological gap. Our extensive simulations demonstrate the validity of SMUT as well as substantial, up to 92%, power gains over alternative methods. In addition, SMUT confirmed known mediators in a real dataset of Finns for plasma adiponectin level, which were missed by many alternative methods. We believe SMUT will become a useful tool to generate mechanistic hypotheses underlying GWAS variants, facilitating functional follow-up. The R package SMUT is publicly available from CRAN at https://CRAN.R-project.org/package=SMUT.

11β-HSD1 reduces metabolic efficacy and adiponectin synthesis in hypertrophic adipocytes

Mitochondrial dysfunction in hypertrophic adipocytes can reduce adiponectin synthesis. We investigated whether 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression is increased in hypertrophic adipocytes and whether this is responsible for mitochondrial dysfunction and reduced adiponectin synthesis. Differentiated 3T3L1 adipocytes were cultured for up to 21 days. The effect of AZD6925, a selective 11β-HSD1 inhibitor, on metabolism was examined. db/db mice were administered 600 mg/kg AZD6925 daily for 4 weeks via gastric lavage. Mitochondrial DNA (mtDNA) content, mRNA expression levels of 11β-Hsd1 and mitochondrial biogenesis factors, adiponectin synthesis, fatty acid oxidation (FAO), oxygen consumption rate and glycolysis were measured. Adipocyte hypertrophy in 3T3L1 cells exposed to a long duration of culture was associated with increased 11β-Hsd1 mRNA expression and reduced mtDNA content, mitochondrial biogenesis factor expression and adiponectin synthesis. These cells displayed reduced mitochondrial respiration and increased glycolysis. Treatment of these cells with AZD6925 increased adiponectin synthesis and mitochondrial respiration. Inhibition of FAO by etomoxir blocked the AZD6925-induced increase in adiponectin synthesis, indicating that 11β-HSD1-mediated reductions in FAO are responsible for the reduction in adiponectin synthesis. The expression level of 11β-Hsd1 was higher in adipose tissues of db/db mice. Administration of AZD6925 to db/db mice increased the plasma adiponectin level and adipose tissue FAO. In conclusion, increased 11β-HSD1 expression contributes to reduced mitochondrial respiration and adiponectin synthesis in hypertrophic adipocytes.