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1.  Adiponectin gene variants, adiponectin isoforms and cardiometabolic risk in type 2 diabetic patients 
Abstract
Aims/Introduction
The aim of the present study was to examine the associations of rs2241766 (+45T>G), rs1501299 (+276G>T), rs17300539 (−11391G>A) and rs182052 (−10069G>A) in the adiponectin (Ad) gene with adiponectin concentrations, and concomitantly the association of these variants with cardiometabolic risk in type 2 diabetic patients of African ancestry.
Materials and Methods
A cross‐sectional study of 200 patients was carried out. Concentrations of total, high (HMW), middle (MMW) and low (LMW) molecular weight adiponectin isoforms were measured. The four polymorphisms were genotyped.
Results
Decreased values were noted for total Ad in overweight, dyslipidemia and coronary artery disease (CAD), for HMW in overweight and dyslipidemia, for MMW in CAD, for LMW in dyslipidemia and CAD, for the percentage HMW/total in overweight, and for MMW:HMW ratio in patients without hypertriglyceridemic waist (HTGW). Significant associations were noted between total Ad, HMW, and HMW/total Ad and rs182052 under a dominant model (P = 0.04, P = 0.03 and P = 0.04, respectively), and between MMW and rs17300539 (P = 0.006). No significant difference in adiponectin concentrations was noted according to rs2241766 and rs1501299 genotypes. Patients carrying the rs2241766 G allele (TG+GG) had an increased risk of HTGW (odds ratio [OR] 3.1; P = 0.04) and of CAD (OR 3.3; P = 0.01). The odds of having low total adiponectin concentrations (<25th percentile: 3.49 ng/mL) for carrying the rs182052A allele (AA+GA) was: OR 0.40; P = 0.009. The single‐nucleotide polymorphism associated with adiponectin levels was not concomitantly associated with cardiometabolic risk factors.
Conclusions
Adiponectin concentrations and ADIPOQ variants are implicated in the pathophysiological process leading to cardiovascular diseases, but the genetic effects seem to be independent of adiponectin concentrations in our Afro–Caribbean diabetic patients.
doi:10.1111/jdi.12133
PMCID: PMC4023583  PMID: 24843760
Adiponectin; Cardiometabolic risk; Diabetes
2.  Genetic Architecture of Plasma Adiponectin Overlaps With the Genetics of Metabolic Syndrome–Related Traits 
Diabetes Care  2010;33(4):908-913.
OBJECTIVE
Adiponectin, a hormone secreted by adipose tissue, is of particular interest in metabolic syndrome, because it is inversely correlated with obesity and insulin sensitivity. However, it is not known to what extent the genetics of plasma adiponectin and the genetics of obesity and insulin sensitivity are interrelated. We aimed to evaluate the heritability of plasma adiponectin and its genetic correlation with the metabolic syndrome and metabolic syndrome–related traits and the association between these traits and 10 ADIPOQ single nucleotide polymorphisms (SNPs).
RESEARCH DESIGN AND METHODS
We made use of a family-based population, the Erasmus Rucphen Family study (1,258 women and 967 men). Heritability analysis was performed using a polygenic model. Genetic correlations were estimated using bivariate heritability analyses. Genetic association analysis was performed using a mixed model.
RESULTS
Plasma adiponectin showed a heritability of 55.1%. Genetic correlations between plasma adiponectin HDL cholesterol and plasma insulin ranged from 15 to 24% but were not significant for fasting glucose, triglycerides, blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR), and C-reactive protein. A significant association with plasma adiponectin was found for ADIPOQ variants rs17300539 and rs182052. A nominally significant association was found with plasma insulin and HOMA-IR and ADIPOQ variant rs17300539 after adjustment for plasma adiponectin.
CONCLUSIONS
The significant genetic correlation between plasma adiponectin and HDL cholesterol and plasma insulin should be taken into account in the interpretation of genome-wide association studies. Association of ADIPOQ SNPs with plasma adiponectin was replicated, and we showed association between one ADIPOQ SNP and plasma insulin and HOMA-IR.
doi:10.2337/dc09-1385
PMCID: PMC2845050  PMID: 20067957
3.  Maternal Serum Adiponectin Multimers in Preeclampsia 
Journal of perinatal medicine  2009;37(4):349-363.
Objective
Obesity, insulin resistance, and dyslipidemia are associated with preeclampsia. Recently, “adipose tissue failure”, characterized by dysregulation of adipokine production, has been implicated in the pathophysiology of these metabolic complications. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine, circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. These multimers exert differential biological effects, and HMW to total adiponectin ratio (SA) has been reported to be a specific marker of adiponectin activity. The aim of this study was to determine whether preeclampsia is associated with changes in circulating adiponectin multimers.
Study design
This cross-sectional study included women with: 1) normal pregnancy (n=225); and 2) patients with mild preeclampsia (n=111). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analysis.
Results
1) The median maternal HMW and LMW adiponectin concentrations were lower in patients with preeclampsia than in those with normal pregnancies (p<0.001 and p=0.01, respectively); 2) patients with preeclampsia had a lower HMW/Total adiponectin ratio (p<0.001) and higher MMW/Total adiponectin and LMW/Total adiponectin ratios than those with a normal pregnancy (p<0.001 and p=0.009, respectively); 3) the presence of preeclampsia was independently associated with lower maternal serum HMW adiponectin concentrations (p=0.001) and with a low HMW/Total adiponectin ratio (p<0.001) after correction for maternal age, maternal BMI, the difference in BMI between the third and the first trimester, and gestational age at sampling; and 4) overweight/obese pregnant women had a lower median total and HMW adiponectin concentration than normal weight pregnant women among women with normal pregnancies, but not among those with preeclampsia.
Conclusion
1) Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/Total adiponectin ratio, a specific marker of adiponectin biologic activity; 2) in contrast to normal pregnancy, preeclampsia is not associated with decreased circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in preeclampsia; 3) collectively, these findings suggest that preeclampsia is characterized by alterations in adiponectin multimers and their relative distribution implying a role for adiponectin multimers in the mechanism of disease in preeclampsia.
doi:10.1515/JPM.2009.085
PMCID: PMC3166229  PMID: 19348608
Adipokines; Pregnancy; High-molecular-weight (HMW) adiponectin; Medium-molecular-weight (MMW) adiponectin; Low-molecular-weight (LMW) adiponectin; BMI; overweight; obesity
4.  Altered distribution of adiponectin isoforms in children with Prader–Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones 
Clinical endocrinology  2007;67(6):944-951.
Summary
Objective
Prader–Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones.
Design, patients and measurements
We measured total adiponectin and its isoforms [high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin] and satiety hormones in 14 children with PWS [median age 11.35 years, body mass index (BMI) Z-score 2.15] and 14 BMI-matched controls (median age 11.97 years, BMI Z-score 2.34).
Results
Despite comparable BMI Z-scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA-IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z-score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0.05), HOMA-IR (P < 0.01), BMI Z-score (P < 0.05), insulin (P < 0.01) and leptin (P < 0.05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls.
Conclusions
Relative to controls of similar age and BMI Z-score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI-matched controls.
doi:10.1111/j.1365-2265.2007.02991.x
PMCID: PMC2605973  PMID: 17666087
5.  Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study 
BMC Medical Genetics  2011;12:5.
Background
Adiponectin, secreted mainly by mature adipocytes, is a protein with insulin-sensitising and anti-atherogenic effects. Human adiponectin is encoded by the ADIPOQ gene on the chromosomal locus 3q27. Variations in ADIPOQ are associated with obesity, type 2 diabetes (T2DM) and related phenotypes in several populations. Our aim was to study the association of the ADIPOQ variations with body weight, serum adiponectin concentrations and conversion to T2DM in overweight subjects with impaired glucose tolerance. Moreover, we investigated whether ADIPOQ gene variants modify the effect of lifestyle changes on these traits.
Methods
Participants in the Finnish Diabetes Prevention Study were randomly assigned to a lifestyle intervention group or a control group. Those whose DNA was available (n = 507) were genotyped for ten ADIPOQ single nucleotide polymorphisms (SNPs). Associations between SNPs and baseline body weight and serum adiponectin concentrations were analysed using the univariate analysis of variance. The 4-year longitudinal weight data were analysed using linear mixed models analysis and the change in serum adiponectin from baseline to year four was analysed using Kruskal-Wallis test. In addition, the association of SNPs with the risk of developing T2DM during the follow-up of 0-11 (mean 6.34) years was analysed by Cox regression analysis.
Results
rs266729, rs16861205, rs1501299, rs3821799 and rs6773957 associated significantly (p < 0.05) with body weight at baseline and in the longitudinal analyses. The rs266729 C allele and the rare minor alleles of rs2241766 and rs2082940 were associated with an increased adjusted hazard ratio of developing T2DM. The differences in baseline serum adiponectin concentrations were seen according to rs16861210, rs17366568, rs2241766, rs6773957 and rs2082940 and differences in the change of serum adiponectin levels from baseline to the four year examination were seen according to rs16861205, especially in subjects who were able to lose weight during the first year of intervention.
Conclusions
These results from the Finnish Diabetes Prevention Study support the concept that genetic variation in ADIPOQ locus contributes to variation in body size and serum adiponectin concentrations and may also modify the risk of developing T2DM.
Trial registration number
ClinicalTrials.gov NCT00518167
doi:10.1186/1471-2350-12-5
PMCID: PMC3032655  PMID: 21219602
6.  Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals 
Dastani, Zari | Hivert, Marie-France | Timpson, Nicholas | Perry, John R. B. | Yuan, Xin | Scott, Robert A. | Henneman, Peter | Heid, Iris M. | Kizer, Jorge R. | Lyytikäinen, Leo-Pekka | Fuchsberger, Christian | Tanaka, Toshiko | Morris, Andrew P. | Small, Kerrin | Isaacs, Aaron | Beekman, Marian | Coassin, Stefan | Lohman, Kurt | Qi, Lu | Kanoni, Stavroula | Pankow, James S. | Uh, Hae-Won | Wu, Ying | Bidulescu, Aurelian | Rasmussen-Torvik, Laura J. | Greenwood, Celia M. T. | Ladouceur, Martin | Grimsby, Jonna | Manning, Alisa K. | Liu, Ching-Ti | Kooner, Jaspal | Mooser, Vincent E. | Vollenweider, Peter | Kapur, Karen A. | Chambers, John | Wareham, Nicholas J. | Langenberg, Claudia | Frants, Rune | Willems-vanDijk, Ko | Oostra, Ben A. | Willems, Sara M. | Lamina, Claudia | Winkler, Thomas W. | Psaty, Bruce M. | Tracy, Russell P. | Brody, Jennifer | Chen, Ida | Viikari, Jorma | Kähönen, Mika | Pramstaller, Peter P. | Evans, David M. | St. Pourcain, Beate | Sattar, Naveed | Wood, Andrew R. | Bandinelli, Stefania | Carlson, Olga D. | Egan, Josephine M. | Böhringer, Stefan | van Heemst, Diana | Kedenko, Lyudmyla | Kristiansson, Kati | Nuotio, Marja-Liisa | Loo, Britt-Marie | Harris, Tamara | Garcia, Melissa | Kanaya, Alka | Haun, Margot | Klopp, Norman | Wichmann, H.-Erich | Deloukas, Panos | Katsareli, Efi | Couper, David J. | Duncan, Bruce B. | Kloppenburg, Margreet | Adair, Linda S. | Borja, Judith B. | Wilson, James G. | Musani, Solomon | Guo, Xiuqing | Johnson, Toby | Semple, Robert | Teslovich, Tanya M. | Allison, Matthew A. | Redline, Susan | Buxbaum, Sarah G. | Mohlke, Karen L. | Meulenbelt, Ingrid | Ballantyne, Christie M. | Dedoussis, George V. | Hu, Frank B. | Liu, Yongmei | Paulweber, Bernhard | Spector, Timothy D. | Slagboom, P. Eline | Ferrucci, Luigi | Jula, Antti | Perola, Markus | Raitakari, Olli | Florez, Jose C. | Salomaa, Veikko | Eriksson, Johan G. | Frayling, Timothy M. | Hicks, Andrew A. | Lehtimäki, Terho | Smith, George Davey | Siscovick, David S. | Kronenberg, Florian | van Duijn, Cornelia | Loos, Ruth J. F. | Waterworth, Dawn M. | Meigs, James B. | Dupuis, Josee | Richards, J. Brent
PLoS Genetics  2012;8(3):e1002607.
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Author Summary
Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.
doi:10.1371/journal.pgen.1002607
PMCID: PMC3315470  PMID: 22479202
7.  Association of the +45T>G and +276G>T polymorphisms in the adiponectin gene with insulin resistance in nondiabetic Greek women 
Objective
We explored potential associations of two single nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ; +45T>G, rs2241766 and +276G>T, rs1501299) with circulating total and high-molecular weight (HMW) adiponectin, insulin resistance (IR), and markers of obesity in a healthy Greek female population.
Design and methods
The two SNPs were genotyped in 349 women without diabetes (mean age: 47.0±12.1 years, mean body mass index: 28.9±5.6 kg/m2). Total and HMW adiponectin concentrations, body composition variables, IR parameters, and plasma lipid levels were determined.
Results
In single SNP analysis adjusting for several potential confounders, SNP +276G>T was associated with higher fasting insulin levels (P = 0.01) and higher homeostasis model assessment index for IR (HOMA-IR; P = 0.009), and SNP +45T>G was associated with lower insulin levels and HOMA-IR (P = 0.05 and P = 0.07 respectively). No association with total or HMW adiponectin, plasma lipid levels, and body composition variables was observed; however, haplotype analysis revealed that subjects homozygous for the most common +45T/+276G haplotype had lower total adiponectin levels than did noncarriers of this haplotype (P = 0.02). The observed differences in HOMA-IR were very significant among women with a higher body fat (BF) percentage (≥ the population median of 41%; all P ≤ 0.005), but not among leaner individuals (P for interactions 0.01–0.07), thus suggesting that ADIPOQ effects on insulin sensitivity may depend upon BF status.
Conclusion
Our data suggest a significant role of ADIPOQ variants at positions +45 and +276 in the development of IR in healthy Greek women possibly through an interaction with BF.
doi:10.1530/EJE-09-0492
PMCID: PMC2896503  PMID: 19755407
8.  Adiponectin pathway polymorphisms and risk of breast cancer in African Americans and Hispanics in the Women’s Health Initiative 
Background
Adiponectin, a protein secreted by the adipose tissue, is an endogenous insulin sensitizer with circulating levels that are decreased in obese and diabetic subjects. Recently, circulating levels of adiponectin have been correlated with breast cancer risk. Our previous work showed that polymorphisms of the adiponectin pathway are associated with breast cancer risk.
Methods
We conducted the first study of adiponectin pathways in African Americans and Hispanics in the Women’s Health Initiative (WHI) SNP Health Association Resource (SHARe) cohort of 3,642 self-identified Hispanic women and 8,515 self-identified African American women who provided consent for DNA analysis. Single nucleotide polymorphisms (SNPs) from three genes were included in this analysis: ADIPOQ, ADIPOR1 and ADIPOR2. The Genome-wide Human SNP Array 6.0 (909,622 SNPs) (www.affymetrix.com) was used.
Results
We found that rs1501299, a functional SNP of ADIPOQ that we previously reported was associated with breast cancer risk in a mostly Caucasian population, was also significantly associated with breast cancer incidence (HR for the GG/TG genotype: 1.23; 95% CI: 1.059–1.43) in African American women. We did not find any other SNPs in these genes to be associated with breast cancer incidence.
Conclusions
This is the first study assessing the role of adiponectin pathway SNPs in breast cancer risk in African Americans and Hispanics. RS1501299 is significantly associated with breast cancer risk in African American women. Impact: As the rates of obesity and diabetes increase in African Americans and Hispanics, adiponectin and its functional SNPs may aid in breast cancer risk assessment.
doi:10.1007/s10549-013-2546-6
PMCID: PMC3773607  PMID: 23624817
adiponectin; polymorphisms; breast cancer; African Americans; Hispanics
9.  Distribution of Adiponectin Multimeric Forms In Chinese Women With Polycystic Ovary Syndrome and Their Relation To Insulin Resistance 
Objective
Adiponectin, an abundant adipokine with insulin sensitizing properties, exists different multimeric forms, including low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW) species. Alterations in the distribution of adiponectin multimers and the relationship between adiponectin multimers and insulin resistance (IR) in women with the polycystic ovary syndrome (PCOS) remain unclear. To compare adiponectin multimerization status and estimate of insulin sensitivity in Chinese women with PCOS compared with age and body mass index (BMI)-matched controls.
Methods
Cross-sectional study involving 64 Chinese women with PCOS and 59 normal women. Circulating total adiponectin and its multimeric forms were determined by ELISA and insulin resistance was estimated using the homeostasis assessment insulin resistance index (HOMA-IR).
Results
After controlling for BMI status, levels of both total and HMW adiponectin were significantly lower in women with PCOS compared with normal women (P<0.05). Furthermore, HMW adiponectin provided a stronger contribution to models predicting insulin resistance than total adiponectin. Lastly, decreased HMW adiponectin was associated with increased HOMA-IR in both normal and PCOS women, and this association was independent of both overall adiposity and visceral adiposity.
Conclusion
Levels of both total and HMW adiponectin are decreased in Chinese women with PCOS compared with normal control women and the differences in HMW adiponectin persists after controlling for BMI. Furthermore, HMW adiponectin is a stronger predictor of insulin resistance in both women with PCOS and normal women than total adiponectin.
doi:10.1530/EJE-10-0021
PMCID: PMC3683393  PMID: 20530094
Polycystic ovary syndrome; adiponectin; insulin resistance; HMW-adiponectin
10.  Calcium Is Involved in Formation of High Molecular Weight Adiponectin 
Background
Adiponectin, an adipocyte-specific secretory protein, is known to circulate as different isoforms in the blood stream.
Methods
Using sucrose gradients and Western blotting on nondenaturing gels, adiponectin isoforms were examined in human serum, plasma, adipose tissue, and cells. The medium from human adipose tissue and human and mouse adipocytes were also examined for changes in isoform formation upon treatment with EGTA.
Results
Comparison of adiponectin complexes revealed distinct differences in distribution of high molecular weight (HMW) forms between human serum and plasma, with an apparent difference in molecular weight. Variation in molecular weight suggested a probable dissociation of the HMW isoforms in the presence of EDTA in the plasma. Examination of human serum samples treated with EDTA or EGTA showed a partial dissociation of the HMW isoform, while the addition of excess calcium, but not magnesium, to human plasma resulted in partial restoration of HMW adiponectin. When human adipose tissue–secreted adiponectin was treated with EGTA, there was a decrease in the HMW isoform by 61% (± 1.89%) and a corresponding increase in low molecular weight (LMW) and middle molecular weight (MMW) isoforms, compared to untreated samples. Analysis of mouse and human adipocytes also showed a reduction in HMW isoforms with a corresponding increase in MMW and LMW isoforms upon treatment with EGTA. The Simpson-Golabi-Behmel syndrome (SGBS) human adipocyte cell line, which primarily synthesizes LMW isoforms, produced increasing amounts of HMW adiponectin upon treatment with calcium in a dose-dependent manner.
Conclusion
These data indicate that calcium promotes the formation of HMW adiponectin, and calcium sequestration decreases HMW adiponectin. Because of the importance of HMW adiponectin in insulin sensitivity, these data demonstrate the importance of assay conditions and sample preparation in the measurement of adiponectin isoforms.
doi:10.1089/met.2007.0033
PMCID: PMC2755550  PMID: 18510435
11.  Calcium Is Involved in Formation of High Molecular Weight Adiponectin 
Abstract
Background
Adiponectin, an adipocyte-specific secretory protein, is known to circulate as different isoforms in the blood stream.
Methods
Using sucrose gradients and Western blotting on nondenaturing gels, adiponectin isoforms were examined in human serum, plasma, adipose tissue, and cells. The medium from human adipose tissue and human and mouse adipocytes were also examined for changes in isoform formation upon treatment with EGTA.
Results
Comparison of adiponectin complexes revealed distinct differences in distribution of high molecular weight (HMW) forms between human serum and plasma, with an apparent difference in molecular weight. Variation in molecular weight suggested a probable dissociation of the HMW isoforms in the presence of EDTA in the plasma. Examination of human serum samples treated with EDTA or EGTA showed a partial dissociation of the HMW isoform, while the addition of excess calcium, but not magnesium, to human plasma resulted in partial restoration of HMW adiponectin. When human adipose tissue–secreted adiponectin was treated with EGTA, there was a decrease in the HMW isoform by 61% (± 1.89%) and a corresponding increase in low molecular weight (LMW) and middle molecular weight (MMW) isoforms, compared to untreated samples. Analysis of mouse and human adipocytes also showed a reduction in HMW isoforms with a corresponding increase in MMW and LMW isoforms upon treatment with EGTA. The Simpson-Golabi-Behmel syndrome (SGBS) human adipocyte cell line, which primarily synthesizes LMW isoforms, produced increasing amounts of HMW adiponectin upon treatment with calcium in a dose-dependent manner.
Conclusion
These data indicate that calcium promotes the formation of HMW adiponectin, and calcium sequestration decreases HMW adiponectin. Because of the importance of HMW adiponectin in insulin sensitivity, these data demonstrate the importance of assay conditions and sample preparation in the measurement of adiponectin isoforms.
doi:10.1089/met.2007.0033
PMCID: PMC2755550  PMID: 18510435
12.  Adiponectin Multimers and Metabolic Syndrome Traits: Relative Adiponectin Resistance in African Americans 
Obesity (Silver Spring, Md.)  2008;16(12):2616-2623.
African Americans (AAs) tend to have lower total adiponectin levels compared to European Americans (EA); however, it is not known whether race affects adiponectin multimer distribution and their relationships to metabolic traits. We measured total adiponectin, high molecular weight (HMW), low molecular weight (LMW) (i.e., hexamer), and trimer adiponectin in 132 normoglycemic premenopausal women (75 AAs, 57 EAs), together with measures of total and abdominal fat, plasma lipids, insulin sensitivity (Si), and genetic admixture estimates. We found that lower total adiponectin in AAs was explained by reduced LMW, and trimer forms because levels of HMW did not differ between races. In EAs, HMW was highly correlated with multiple metabolic syndrome traits. In contrast, the LMW and trimer forms were most highly correlated with metabolic traits in AAs, including abdominal adiposity, lipids, and Si. At similar levels of visceral adiposity, AAs exhibited significantly lower LMW adiponectin than EAs. Similarly, at comparable levels of HMW and LMW adiponectin, AAs were more insulin resistant than their EA counterparts. In conclusion, (i) serum adiponectin is lower in AAs predominantly as a result of reduced concentrations of LMW and trimers multimeric forms; (ii) LMW and trimer, not HMW, are most broadly correlated with metabolic traits in AAs. Thus, HMW adiponectin may exert less bioactivity in explaining the metabolic syndrome trait cluster in populations of predominant African genetic background.
doi:10.1038/oby.2008.411
PMCID: PMC2721223  PMID: 18820653
13.  ASSOCIATION BETWEEN ADIPOQ SNPS WITH PLASMA ADIPONECTIN AND GLUCOSE HOMEOSTASIS AND ADIPOSITY PHENOTYPES IN THE IRAS FAMILY STUDY 
Molecular genetics and metabolism  2012;107(4):721-728.
Context
Adiponectin is an adipocytokine associated with a variety of metabolic traits. These associations in human studies, in conjunction with functional studies in model systems, have implicated adiponectin in multiple metabolic processes.
Objective
We hypothesize that genetic variants associated with plasma adiponectin would also be associated with glucose homeostasis and adiposity phenotypes.
Design and Setting
The Insulin Resistance Atherosclerosis Family Study was designed to identify the genetic and environmental basis of insulin resistance and adiposity in the Hispanic- (n=1,424) and African-American (n=604) population.
Main Outcome Measures
High quality metabolic phenotypes, e.g. insulin sensitivity (SI), acute insulin response (AIR), disposition index (DI), fasting glucose, body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and waist circumference, were explored.
Results
Based on association analysis of more than 40 genetic polymorphisms in the adiponectin gene (ADIPOQ), we found no consistent association of ADIPOQ variants with plasma adiponectin levels and adiposity phenotypes. However, there were two promoter variants, rs17300539 and rs822387, associated with plasma adiponectin levels (P=0.0079 and 0.021, respectively) in the Hispanic-American cohort that were also associated with SI (P=0.0067 and 0.013, respectively). In contrast, there was only a single promoter SNP, rs17300539, associated with plasma adiponectin levels (P=0.0018) and fasting glucose (P=0.042) in the African-American cohort. Strikingly, high impact coding variants did not show evidence of association.
Conclusions
The lack of consistent patterns of association between variants, adiponectin levels, glucose homeostasis, and adiposity phenotypes suggests a reassessment of the influence of adiponectin in these pathways.
doi:10.1016/j.ymgme.2012.10.003
PMCID: PMC3504195  PMID: 23102667
adiponectin; single nucleotide polymorphisms; glucose homeostasis; adiposity; African Americans; Hispanic Americans
14.  Adiponectin gene ADIPOQ SNP associations with serum adiponectin in two female populations and effects of SNPs on promoter activity 
Journal of human genetics  2008;53(8):718-727.
Adiponectin is an insulin sensitizer in muscle and liver and low serum levels characterise obesity and insulin resistance. Eight tagging SNPs in the ADIPOQ gene and promoter were selected and association with serum adiponectin was tested in two independent samples of Caucasian females: the Chingford Study (n=808, mean age 62.8±5.9 years) and Twins UK (n=2718, mean age 47.4±12.6 years). In the Chingford cohort, −11391 G/A, −10066 G/A (rs182052), −7734 C/A (rs16861209), +276 G/T (rs1501299) and +3228 C/T (rs1063537) were significantly associated with fasting serum adiponectin (Ps=1.00 × 10−4 to 1.40 × 10−2). Associations with all except +3228 C/T were replicated in the Twins UK cohort (Ps=3.19 × 10−9 to 6.00 × 10−3). In Chingford subjects, the twelve most common 8-SNP haplotypes (freq. 1.90%) explained 2.85% (p=5.00 × 10−2) and in Twins UK subjects, the four most common 5-SNP haplotypes (freq. >5.00%) explained 1.66% of the variance (p=5.83 × 10−7). To investigate effects of −11391 G/A (rs17300539) and −11377 C/G (rs266729) on promoter activity, 1.2 kb of the ADIPOQ promoter region was cloned in a luciferase reporter plasmid and the four haplotypes were transfected in differentiated 3T3-L1 adipocytes. No significant allelic effects on promoter activity were found.
doi:10.1007/s10038-008-0303-1
PMCID: PMC2564110  PMID: 18523726
adiponectin; gene transfection; genetic epidemiology; metabolic syndrome; single nucleotide polymorphism
15.  DYSREGULATION OF MATERNAL SERUM ADIPONECTIN IN PRETERM LABOR 
Objective
Intra-amniotic and systemic infection/inflammation have been causally linked to preterm parturition and fetal injury. An emerging theme is that adipose tissue can orchestrate a metabolic response to insults, but also an inflammatory response via the production of adipocytokines, and that these two phenomenon are interrelated. Adiponectin, an insulin-sensitizing, anti-inflammatory adipocytokine, circulates in multimeric complexes including low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. Each of these complexes can exert differential biological effects. The aim of this study was to determine whether spontaneous preterm labor (PTL) with intact membranes and intra-amniotic infection/inflammation (IAI) is associated with changes in maternal serum circulating adiponectin multimers.
Study design
This cross-sectional study included patients in the following groups: 1) normal pregnant women (n=158); 2) patients with an episode of preterm labor and intact membranes without IAI who delivered at term (n=41); 3) preterm labor without IAI who delivered preterm (n=27); and 4) preterm labor with IAI who delivered preterm (n=36). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analyses.
Results
1) Preterm labor leading to preterm delivery or an episode of preterm labor which does not lead to preterm delivery, was associated with a lower median maternal serum concentration of total and HMW adiponectin, a lower median HMW/total adiponectin ratio, and a higher median LMW/total adiponectin ratio than normal pregnancy; 2) among patients with preterm labor, those with IAI had the lowest median concentration of total and HMW adiponectin, as well as the lowest median HMW/total adiponectin ratio; 3) The changes in maternal adiponectin and adiponectin multimers remained significant after adjusting for confounding factors such as maternal age, BMI, gestational age at sampling, and parity.
Conclusion
1) Preterm labor is characterized by a change in the profile of adiponectin multimers concentrations and their relative isoforms. These changes were observed in patients with an episode of preterm labor not leading to preterm delivery, in patients with intra-amniotic inflammation, or in those without evidence of intra-amniotic inflammation; 2) The changes in adiponectin multimer concentrations reported in preterm labor are different from those previously reported in spontaneous labor at term, suggesting that there is a fundamental difference between preterm labor and labor at term; 3) The findings reported herein, provide the first evidence for the participation of adiponectin multimer in preterm parturition. We propose that adiponectins and adipokines in general provide a mechanism to organize the metabolic demands generated by the process of preterm parturition regardless of the nature of the insult (intra-amniotic inflammation or not).
doi:10.1080/14767050902994655
PMCID: PMC3600360  PMID: 19579094
Adiponectin; Adipokines; Pregnancy; High molecular weight (HMW); Medium molecular weight (MMW); Low molecular weight (LMW); Preterm labor; Intra-amniotic infection; Inflammation; Chorioamnionitis; Preterm delivery; Energy Requirements; Energy Expenditure; Preterm Birth; Metabolism; Metaflammation
16.  Total and High-Molecular Weight Adiponectin in Women with the Polycystic Ovary Syndrome 
Objective
Adiponectin, an adipokine with antidiabetic properties, forms multimers, and the high molecular weight (HMW) form most closely correlates with insulin sensitivity. Therefore, we hypothesize that HMW adiponectin levels are decreased in women with polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance, compared to normal controls, and that HMW adiponectin correlates with testosterone and insulin sensitivity.
Design and patients
Cross-sectional study involving 13 women with PCOS and 13 age- and BMI-matched normal controls.
Measurements
Waist-to-hip ratios (WHR), glucose, insulin, SHBG, total testosterone, total and HMW adiponectin levels were measured after an overnight fast. Free testosterone was calculated from SHBG and total testosterone, and insulin sensitivity (Si) was determined using a frequently sampled intravenous glucose tolerance test. The study’s primary outcomes were differences in total and HMW adiponectin between women with PCOS and normal control women.
Results
Total adiponectin (p<0.01), HMW adiponectin (p<0.01), and the ratio of HMW to total adiponectin (SA) (p=0.03), were lower in women with PCOS compared to normal women. Total and HMW adiponectin levels correlated inversely with WHR (p<0.01) and free testosterone (p<0.01) and positively with Si (p<0.001). Using forward stepwise multivariate analysis, HMW adiponectin and WHR, but not PCOS status, were independent predictors of Si.
Conclusions
Women with PCOS have lower total and HMW adiponectin levels compared with normal women. HMW adiponectin also comprises a smaller proportion of total circulating adiponectin in women with PCOS. Alterations in HMW adiponectin levels in women with PCOS may contribute to the insulin resistance intrinsic to the syndrome.
doi:10.1016/j.metabol.2010.02.019
PMCID: PMC2946975  PMID: 20359725
adiponectin multimers; insulin sensitivity; testosterone; visceral adiposity
17.  Novel Locus FER Is Associated With Serum HMW Adiponectin Levels 
Diabetes  2011;60(8):2197-2201.
OBJECTIVE
High molecular weight (HMW) adiponectin is a predominant isoform of circulating adiponectin and has been related to type 2 diabetes. Previous linkage studies suggest that different genetic components might be involved in determining HMW and total adiponectin levels.
RESEARCH DESIGN AND METHODS
We performed a genome-wide association study (GWAS) of serum HMW adiponectin levels in individuals of European ancestry drawn from the Nurses’ Health Study (NHS) (N = 1,591). The single nucleotide polymorphisms (SNPs) identified in the GWAS analysis were replicated in an independent cohort of Europeans (N = 626). We examined the associations of the identified variations with diabetes risk and metabolic syndrome.
RESULTS
We identified a novel locus near the FER gene (5q21) at a genome-wide significance level, best represented by SNP rs10447248 (P = 4.69 × 10−8). We also confirmed that variations near the adiponectin-encoding ADIPOQ locus (3q27) were related to serum HMW adiponectin levels. In addition, we found that FER SNP rs10447248 was related to HDL cholesterol levels (P = 0.009); ADIPOQ variation was associated with fasting glucose (P = 0.04), HDL cholesterol (P = 0.04), and a metabolic syndrome score (P = 0.002).
CONCLUSIONS
Our results suggest that different loci may be involved in regulation of circulating HMW adiponectin levels and provide novel insight into the mechanisms that affect HMW adiponectin homeostasis.
doi:10.2337/db10-1645
PMCID: PMC3142072  PMID: 21700879
18.  ADIPOQ, ADIPOR1, and ADIPOR2 Polymorphisms in Relation to Serum Adiponectin Levels and Body Mass Index in Black and White Women 
Obesity (Silver Spring, Md.)  2011;19(10):2053-2062.
Adiponectin is an adipose-secreted protein with influence on several physiologic pathways including those related to insulin sensitivity, inflammation, and atherogenesis. Adiponectin levels are highly heritable and several single nucleotide polymorphisms (SNPs) in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined in relation to circulating adiponectin levels and obesity phenotypes, but despite differences in adiponectin levels and obesity prevalence by race, few studies have included black participants. Using cross-sectional interview data and blood samples collected from 990 black and 977 white women enrolled in the Southern Community Cohort Study from 2002 to 2006, we examined 25 SNPs in ADIPOQ, 19 in ADIPOR1, and 27 in ADIPOR2 in relation to serum adiponectin levels and body mass index (BMI) using race-stratified linear regression models adjusted for age and percentage African ancestry. SNP rs17366568 in ADIPOQ was significantly associated with serum adiponectin levels in white women only (adjusted mean adiponectin levels = 15.9 for G/G genotype, 13.7 for A/G, and 9.3 for A/A, p=0.00036). No other SNPs were associated with adiponectin or BMI among blacks or whites. Because adiponectin levels as well as obesity are highly heritable and vary by race but associations with polymorphisms in the ADIPOQ, ADIPOR1, and ADIPOR2 genes have been few in this and other studies, future work including large populations from diverse racial groups is needed to detect additional genetic variants that influence adiponectin and BMI.
doi:10.1038/oby.2010.346
PMCID: PMC3474141  PMID: 21273992
Adiponectin; obesity; genetics; African Americans
19.  MATERNAL SERUM ADIPONECTIN MULTIMERS IN PATIENTS WITH A SMALL-FOR-GESTATIONAL-AGE NEWBORN 
Journal of perinatal medicine  2009;37(6):623-635.
Objective
Several mechanisms of disease have been implicated in the pathophysiology of SGA including an anti-angiogenic state, failure of physiologic transformation of spiral arteries, and an exaggerated intravascular pro-inflammatory response. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine circulates in oligomeric complexes including low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. Adiponectin plays a role in a wide range of biological activities including those that have been implicated in the pathophysiology SGA. Thus, the aim of this study was to determine if third trimester adiponectin concentrations differed between women with normal weight infants and those with an SGA neonate.
Study design
This cross-sectional study included women with: 1) a normal pregnancy (n=234); and 2) an SGA neonate (n=78). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Maternal serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analyses.
Results
1) The median maternal serum concentrations of total, HMW and MMW adiponectin were significantly lower in patients with an SGA neonate than in those with normal pregnancies; 2) patients with an SGA neonate had a significantly lower median HMW/total adiponectin ratio and higher median MMW/total adiponectin and LMW/total adiponectin ratios than those with a normal pregnancy; 3) among patients with an SGA neonate, neither maternal serum concentrations of adiponectin multimers, nor their relative distribution differ between normal weight and overweight/obese patients.
Conclusion
1) Pregnancies complicated by an SGA neonate are characterized by a alterations in the maternal serum adiponectin multimers concentrations and their relative abundance; 2) in contrast to normal pregnancies, those complicated by an SGA neonate are not associated with low circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in the presence of an SGA neonate; 3) collectively, the findings reported herein suggest that maternal adipose tissue may play a role, in the pathogenesis of SGA.
doi:10.1515/JPM.2009.128
PMCID: PMC3594513  PMID: 19530958
Adipokines; Pregnancy; High-molecular-weight (HMW) adiponectin; Medium-molecular-weight (MMW) adiponectin; Low-molecular-weight (LMW) adiponectin; BMI; overweight; obesity; fetal growth; SGA; pregnancy; Adipose tissue
20.  Paradoxically Low Levels of Total and HMW Adiponectin in Relation to Metabolic Parameters in a Tongan Population 
ISRN Endocrinology  2013;2013:873507.
Aim. Adiponectin has demonstrated anti-inflammatory and insulin sensitising properties, and low circulating levels may be an important risk factor for diabetes. We examined levels of adiponectin and its insulin-sensitising HMW isoform and their relationship with metabolic parameters in Tongans, a population prone to type II diabetes. Methods. Adiponectin and its HMW isoform were quantitated by Elisa in specimens from a randomly recruited, multistage cluster population survey of Tongans and from a group of Caucasians. Anthropometric, clinical, and biochemical data were collected on each subject. Results. Both male and female Tongans had lower levels of total and HMW adiponectin than their Caucasian counterparts. Levels of total and HMW adiponectin were higher in females than males in each group. Adiponectin levels were inversely related to BMI, weight, and HOMA in Tongan males and females, as well as to dyslipidemia in both sexes. Conclusion. Tongans had lower levels of both total and HMW adiponectin than Caucasians population, even after matching Tongans to their Caucasian counterparts based on BMI, age, and sex. These findings may reflect differences in body composition between the populations not adequately assessed by BMI, lifestyle factors, or a genetic variant likely in a genetically homogenous population.
doi:10.1155/2013/873507
PMCID: PMC3727086  PMID: 23936666
21.  Adiponectin Is Inversely Associated With Intramyocellular and Intrahepatic Lipids in Obese Premenopausal Women 
Obesity (Silver Spring, Md.)  2010;19(5):911-916.
Adiponectin, an adipokine secreted by adipocytes, exerts beneficial effects on glucose and lipid metabolism and has been found to improve insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. Adiponectin is found in several isoforms and the high-molecular weight (HMW) form has been linked most strongly to the insulin-sensitizing effects. Fat content in skeletal muscle (intramyocellular lipids, IMCL) and liver (intrahepatic lipids, IHL) can be quantified noninvasively using proton magnetic resonance spectroscopy (1H-MRS). The purpose of our study was to assess the relationship between HMW adiponectin and measures of glucose homeostasis, IMCL and IHL, and to determine predictors of adiponectin levels. We studied 66 premenopausal women (mean BMI 31.0 ± 6.6 kg/m2) who underwent 1H-MRS of calf muscles and liver for IMCL and IHL, computed tomography (CT) of the abdomen for abdominal fat depots, dual-energy X-ray absorptiometry (DXA) for fat and lean mass assessments, HMW and total adiponectin, fasting lipid profile and an oral glucose tolerance test (homeostasis model assessment of insulin resistance (HOMAIR), glucose and insulin area under the curve). There were strong inverse associations between HMW adiponectin and measures of insulin resistance, IMCL and IHL, independent of visceral adipose tissue (VAT) and total body fat. IHL was the strongest predictor of adiponectin and adiponectin was a predictor of HOMAIR. Our study showed that in premenopausal obese women HMW adiponectin is inversely associated with IMCL and IHL content. This suggests that adiponectin exerts positive effects on insulin sensitivity in obesity by decreasing intracellular triglyceride content in skeletal muscle and liver; it is also possible that our results reflect effects of insulin on adiponectin.
doi:10.1038/oby.2010.296
PMCID: PMC3607306  PMID: 21151017
22.  Polymorphisms of ADIPOQ and ADIPOR1 and prostate cancer risk 
Objective
Studies have linked prostate cancer risk with insulin resistance and obesity. Circulating levels of adiponectin, a protein involved in insulin resistance and obesity, have been associated with prostate cancer risk. We studied the association of prostate cancer risk with haplotype tagging single nucleotide polymorphisms (SNPs) of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) chosen based on their functional relevance or association with other types of cancer.
Materials-Methods
DNA samples from 465 cases and 441 healthy volunteers from New York City were genotyped for ADIPOQ rs266729, rs822395, rs822396, rs1501299 and rs2241766 SNPs and ADIPOR1 rs12733285, rs1342387, rs7539542, rs2232853 and rs10920531 SNPs. We performed both single and multiple SNP analyses.
Results
We found that rs12733285, rs7539452, rs266729, rs822395, rs822396 and rs1501299 were significantly associated with prostate cancer risk. Haplotype analysis confirmed these results and identified five ADIPOQ 4-SNP haplotypes and one ADIPOR1 2-SNP haplotype tightly associated with prostate cancer risk. Importantly two ADIPOQ SNPs, rs266729 and rs1501299 have been previously associated with colon and breast cancer risk, respectively, in the same direction as in this study.
Conclusions
These findings suggest that variants of the adiponectin pathway may be associated with susceptibility to various forms of common cancers and warrant validation studies.
doi:10.1016/j.metabol.2011.01.005
PMCID: PMC3134585  PMID: 21397927
23.  A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels 
PLoS Genetics  2009;5(12):e1000768.
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
Author Summary
Through a meta-analysis of genome-wide association studies of 14,733 individuals, we identified common base-pair variants in the genome which influence circulating adiponectin levels. Since adiponectin is an adipocyte-derived circulating protein which has been inversely associated with risk of obesity-related diseases such as type 2 diabetes (T2D) and coronary heart disease (CHD), we next sought to understand if the identified variants influencing adiponectin levels also influence risk of T2D, CHD, and several metabolic traits. In addition to confirming that variation at the ADIPOQ locus influences adiponectin levels, our analyses point to a variant in the ARL15 (ADP-ribosylation factor-like 15) locus which decreases adiponectin levels and increases risk of CHD and T2D. Further, this same variant was associated with increased fasting insulin levels and glycated hemoglobin. While the function of ARL15 is not known, we provide insight into the tissue specificity of ARL15 expression. These results thus provide novel insights into the physiology of the adiponectin pathway and obesity-related diseases.
doi:10.1371/journal.pgen.1000768
PMCID: PMC2781107  PMID: 20011104
24.  Variants of the Adiponectin and Adiponectin Receptor 1 Genes and Breast Cancer Risk 
Cancer research  2008;68(9):3178-3184.
Breast cancer risk is higher among obese women and women with diabetes. Adiponectin is a protein exclusively secreted by adipose tissue, circulating levels of which have been associated with breast cancer risk. Whether genetic variants within the adiponectin pathway are associated with breast cancer risk is unknown. To explore the association of genetic variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes with breast cancer risk, we conducted a case control study of female patients with breast cancer and healthy female controls from New York City recruited between 1999 and 2004. We genotyped 733 hospital-based breast cancer cases and 839 controls for 10 haplotype-tagging single nucleotide polymorphisms (SNP) of ADIPOQ and ADIPOR1. Two ADIPOQ SNPs (rs2241766 and rs1501299), which have been associated with circulating levels of adiponectin, were associated with breast cancer risk [rs1501299*GG: odd ratios (OR), 1.80; 95% confidence interval (95% CI), 1.14–2.85; rs2241766*TG: OR, 0.61; 95% CI, 0.46–0.80]. One ADIPOR1 SNP (rs7539542), which modulates expression of adiponectin receptor 1 mRNA, was also associated with breast cancer risk (OR, 0.51; 95% CI, 0.28–0.92). Based on the known function of rs2241766 and rs1501299, we categorized individuals by adiponectin signaling status and found that, when compared with high signalers, intermediate signalers had a 4.16-fold increase in breast cancer risk (95% CI, 0.49–35.19), and low signalers had a 6.56-fold increase in breast cancer risk (95% CI, 0.78–54.89; Ptrend = 0.001). This is the first report of an association between functionally relevant variants of the adiponectin pathway and breast cancer risk. The results warrant further studies of the adiponectin pathway in breast cancer.
doi:10.1158/0008-5472.CAN-08-0533
PMCID: PMC2685173  PMID: 18451143
25.  Maternal Serum Adiponectin Multimers In Gestational Diabetes 
Journal of perinatal medicine  2009;37(6):637-650.
Objective
Adiponectin, an adipokine with profound insulin-sensitizing effect, consists of heterogeneous species of multimers. These oligomeric complexes circulate as low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms and can exert differential biological effects. The aims of this study were to determine whether there is a change in circulating adiponectin multimers in the presence of gestational diabetes mellitus (GDM), overweight/obesity or with a treatment with sulfonylurea or insulin in patients with GDM.
Study design
This cross-sectional study included women with: 1) normal pregnancy (n=149); and 2) patients with GDM (n=72). Thirty three patients with GDM were managed with diet alone. Among the others 39 diabetic patients, 17 were treated with Glyburide and 22 with insulin. The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA.
Results
1) The median maternal serum of total, HMW, MMW and LMW were lower in patients with GDM than in those with normal pregnancies (p<0.001 for all comparisons); 2) patients with GDM had a lower HMW/Total adiponectin ratio and a higher MMW/Total and LMW/Total adiponectin ratio than those with a normal pregnancy (p<0.001 for all comparisons); and 3) among GDM patients, there were no differences in the concentrations and relative distribution of adiponectin multimers between those who were managed with diet, and those who were treated with pharmacological agents.
Conclusion
1) GDM is characterized by a distinctive pattern of concentrations and relative distribution of adiponectin multimers akin to Type-2 diabetes mellitus; 2) dysregulation of adiponectin multimeres can provide a mechanistic basis for the association between adiposity and GDM.
doi:10.1515/JPM.2009.101
PMCID: PMC3593069  PMID: 19530957
Adipokines; Pregnancy; High-molecular-weight (HMW) adiponectin; Medium-molecular-weight (MMW) adiponectin; Low-molecular-weight (LMW) adiponectin; BMI; Gestational Diabetes; Diabetes; Overweight; Obesity

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