Search Results

1. Zinc-α2-Glycoprotein Is Unrelated to Gestational Diabetes: Anthropometric and Metabolic Determinants in Pregnant Women and Their Offspring

PLoS ONE 2012;7(12):e47601.

Context

Zinc-α2-Glycoprotein (ZAG) is an adipokine with lipolytic action and is positively associated with adiponectin in adipose tissue. We hypothesize that ZAG may be related with hydrocarbonate metabolism disturbances observed in gestational diabetes mellitus (GDM).

Objective

The aim of this study was to analyze serum ZAG concentration and its relationship with carbohydrate metabolism in pregnant women and its influence on fetal growth.

Design

207 pregnant women (130 with normal glucose tolerance (NGT) and 77 with GDM) recruited in the early third trimester and their offspring were studied. Cord blood was obtained at delivery and neonatal anthropometry was assessed in the first 48 hours. ZAG was determined in maternal serum and cord blood.

Results

ZAG concentration was lower in cord blood than in maternal serum, but similar concentration was observed in NGT and GDM pregnant women. Also similar levels were found between offspring of NGT and GDM women. In the bivariate analysis, maternal ZAG (mZAG) was positively correlated with adiponectin and HDL cholesterol, and negatively correlated with insulin and triglyceride concentrations, and HOMA index. On the other hand, cord blood ZAG (cbZAG) was positively correlated with fat-free mass, birth weight and gestational age at delivery. After adjusting for confounding variables, gestational age at delivery and HDL cholesterol emerged as the sole determinants of cord blood ZAG and maternal ZAG concentrations, respectively.

Conclusion

mZAG was not associated with glucose metabolism during pregnancy. ZAG concentration was lower in cord blood compared with maternal serum. cbZAG was independently correlated with gestational age at delivery, suggesting a role during the accelerated fetal growth during latter pregnancy.

doi:10.1371/journal.pone.0047601

PMCID: PMC3525576 PMID: 23272038

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2. FABP4 Dynamics in Obesity: Discrepancies in Adipose Tissue and Liver Expression Regarding Circulating Plasma Levels

PLoS ONE 2012;7(11):e48605.

Background

FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile.

Objective

In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed.

Methods

The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot.

Results

In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group.

Conclusion

The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity.

doi:10.1371/journal.pone.0048605

PMCID: PMC3489666 PMID: 23139800

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3. Maternal and Cord Blood Adiponectin Multimeric Forms in Gestational Diabetes Mellitus

Diabetes Care 2011;34(11):2418-2423.

OBJECTIVE

To analyze the relationship between maternal adiponectin (mAdiponectin) and cord blood adiponectin (cbAdiponectin) multimeric forms (high molecular weight [HMW], medium molecular weight [MMW], and low molecular weight [LMW]) in a cohort of gestational diabetes mellitus (GDM) and normal glucose–tolerant (NGT) pregnant women.

RESEARCH DESIGN AND METHODS

A total of 212 women with a singleton pregnancy, 132 with NGT and 80 with GDM, and their offspring were studied. Maternal blood was obtained in the early third trimester and cord blood was obtained at delivery. Total adiponectin and the multimeric forms of adiponectin were determined in cord blood and maternal serum. Spearman rank correlation and stepwise linear correlation analysis were used to assess the relationship between cbAdiponectin levels and clinical and analytical parameters.

RESULTS

No differences in cbAdiponectin concentration or its multimeric forms were observed in the offspring of diabetic mothers compared with NGT mothers. The HMW-to-total adiponectin ratio was higher in cord blood than in maternal serum, whereas the MMW- and LMW-to-total adiponectin ratio was lower. Cord blood total and HMW adiponectin levels were positively correlated with birth weight and the ponderal index (PI), whereas cord blood MMW adiponectin was negatively correlated with the PI. In addition, cbAdiponectin and its multimeric forms were correlated with mAdiponectin concentrations. In the multivariate analysis, maternal multimeric forms of adiponectin emerged as independent predictors of cbAdiponectin, its multimers, and their distribution.

CONCLUSIONS

cbAdiponectin concentrations are independently related to mAdiponectin levels and unrelated to the diagnosis of GDM. Maternal multimeric forms of adiponectin are independent predictors of the concentrations of cbAdiponectin and its multimeric forms at delivery.

doi:10.2337/dc11-0788

PMCID: PMC3198272 PMID: 21911780

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4. Serum Levels of TWEAK and Scavenger Receptor CD163 in Type 1 Diabetes Mellitus: Relationship with Cardiovascular Risk Factors. A Case-Control Study

PLoS ONE 2012;7(8):e43919.

Objective

To test the usefulness of serum concentrations of tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and soluble scavenger receptor CD163 (sCD163) as markers of subtle inflammation in patients with type 1 diabetes mellitus (T1DM) without clinical cardiovascular (CV) disease and to evaluate their relationship with arterial stiffness (AS).

Methods

Sixty-eight patients with T1DM and 68 age and sex-matched, healthy subjects were evaluated. Anthropometrical variables and CV risk factors were recorded. Serum concentrations of sTWEAK and sCD163 were measured. AS was assessed by aortic pulse wave velocity (aPWV). All statistical analyses were stratified by gender.

Results

T1DM patients showed lower serum concentrations of sTWEAK (Men: 1636.5 (1146.3–3754.8) pg/mL vs. 765.9 (650.4–1097.1) pg/mL; p<0.001. Women: 1401.0 (788.0–2422.2) pg/mL vs. 830.1 (562.6–1175.9) pg/mL; p = 0.011) compared with their respective controls. Additionally, T1DM men had higher serum concentrations of sCD163 (285.0 (247.7–357.1) ng/mL vs. 224.8 (193.3–296.5) ng/mL; p = 0.012) compared with their respective controls. sTWEAK correlated negatively with aPWV in men (r = −0.443; p<0.001). However, this association disappeared after adjusting for potential confounders. In men, the best multiple linear regression model showed that the independent predictors of sTWEAK were T1DM and WHR (R2 = 0.640; p<0.001). In women, T1DM and SBP were the independent predictors for sTWEAK (R2 = 0.231; p = 0.001).

Conclusion

sTWEAK is decreased in T1DM patients compared with age and sex-matched healthy subjects after adjusting for classic CV risk factors, although sTWEAK levels may be partially influenced by some of them. Additionally, T1DM men have higher serum concentrations of sCD163. These results point out an association between the inflammatory system and CV risk in T1DM.

doi:10.1371/journal.pone.0043919

PMCID: PMC3427173 PMID: 22937125

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5. CD14 Modulates Inflammation-Driven Insulin Resistance

Diabetes 2011;60(8):2179-2186.

OBJECTIVE

The study objective was to evaluate the possible role of the macrophage molecule CD14 in insulin resistance.

RESEARCH DESIGN AND METHODS

The effects of recombinant human soluble CD14 (rh-sCD14) on insulin sensitivity (clamp procedure) and adipose tissue gene expression were evaluated in wild-type (WT) mice, high fat–fed mice, ob/ob mice, and CD14 knockout (KO) mice. We also studied WT mice grafted with bone marrow stem cells from WT donor mice and CD14 KO mice. Finally, CD14 was evaluated in human adipose tissue and during differentiation of human preadipocytes.

RESULTS

rh-sCD14 led to increased insulin action in WT mice, high-fat–fed mice, and ob/ob mice, but not in CD14 KO mice, in parallel to a marked change in the expression of 3,479 genes in adipose tissue. The changes in gene families related to lipid metabolism were most remarkable. WT mice grafted with bone marrow stem cells from WT donor mice became insulin resistant after a high-fat diet. Conversely, WT mice grafted with cells from CD14 KO mice resisted the occurrence of insulin resistance in parallel to decreased mesenteric adipose tissue inflammatory gene expression. Glucose intolerance did not worsen in CD14 KO mice grafted with bone marrow stem cells from high fat–fed WT mice when compared with recipient KO mice grafted with cells from CD14 KO donor mice. CD14 gene expression was increased in whole adipose tissue and adipocytes from obese humans and further increased after tumor necrosis factor-α.

CONCLUSIONS

CD14 modulates adipose tissue inflammatory activity and insulin resistance.

doi:10.2337/db10-1210

PMCID: PMC3142089 PMID: 21700881

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6. Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels

BMC Physiology 2012;12:4.

Background

The expansion of adipose tissue is linked to the development of its vasculature, which appears to have the potential to regulate the onset of obesity. However, at present, there are no studies highlighting the relationship between human adipose tissue angiogenesis and obesity-associated insulin resistance (IR).

Results

Our aim was to analyze and compare angiogenic factor expression levels in both subcutaneous (SC) and omentum (OM) adipose tissues from morbidly obese patients (n = 26) with low (OB/L-IR) (healthy obese) and high (OB/H-IR) degrees of IR, and lean controls (n = 17). Another objective was to examine angiogenic factor correlations with obesity and IR.

Here we found that VEGF-A was the isoform with higher expression in both OM and SC adipose tissues, and was up-regulated 3-fold, together with MMP9 in OB/L-IR as compared to leans. This up-regulation decreased by 23% in OB/-H-IR compared to OB/L-IR. On the contrary, VEGF-B, VEGF-C and VEGF-D, together with MMP15 was down-regulated in both OB/H-IR and OB/L-IR compared to lean patients. Moreover, MMP9 correlated positively and VEGF-C, VEGF-D and MMP15 correlated negatively with HOMA-IR, in both SC and OM.

Conclusion

We hereby propose that the alteration in MMP15, VEGF-B, VEGF-C and VEGF-D gene expression may be caused by one of the relevant adipose tissue processes related to the development of IR, and the up-regulation of VEGF-A in adipose tissue could have a relationship with the prevention of this pathology.

doi:10.1186/1472-6793-12-4

PMCID: PMC3382430 PMID: 22471305

Vascular Endothelial Growth Factor and Metalloproteinase; Obesity; Insulin Resistance; Omentum Adipose Tissue; Subcutaneous Adipose Tissue

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7. Zinc-Alpha 2-Glycoprotein Gene Expression in Adipose Tissue Is Related with Insulin Resistance and Lipolytic Genes in Morbidly Obese Patients

PLoS ONE 2012;7(3):e33264.

Objective

Zinc-α2 glycoprotein (ZAG) stimulates lipid loss by adipocytes and may be involved in the regulation of adipose tissue metabolism. However, to date no studies have been made in the most extreme of obesity. The aims of this study are to analyze ZAG expression levels in adipose tissue from morbidly obese patients, and their relationship with lipogenic and lipolytic genes and with insulin resistance (IR).

Methods

mRNA expression levels of PPARγ, IRS-1, IRS-2, lipogenic and lipolytic genes and ZAG were quantified in visceral (VAT) and subcutaneous adipose tissue (SAT) of 25 nondiabetic morbidly obese patients, 11 with low IR and 14 with high IR. Plasma ZAG was also analyzed.

Results

The morbidly obese patients with low IR had a higher VAT ZAG expression as compared with the patients with high IR (p = 0.023). In the patients with low IR, the VAT ZAG expression was greater than that in SAT (p = 0.009). ZAG expression correlated between SAT and VAT (r = 0.709, p<0.001). VAT ZAG expression was mainly predicted by insulin, HOMA-IR, plasma adiponectin and expression of adiponectin and ACSS2. SAT ZAG expression was only predicted by expression of ATGL.

Conclusions

ZAG could be involved in modulating lipid metabolism in adipose tissue and is associated with insulin resistance. These findings suggest that ZAG may be a useful target in obesity and related disorders, such as diabetes.

doi:10.1371/journal.pone.0033264

PMCID: PMC3307730 PMID: 22442679

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8. De Novo Lipogenesis in Adipose Tissue Is Associated with Course of Morbid Obesity after Bariatric Surgery

PLoS ONE 2012;7(2):e31280.

Objective

De novo lipogenesis is involved in fatty acid biosynthesis and could be involved in the regulation of the triglyceride storage capacity of adipose tissue. However, the association between lipogenic and lipolytic genes and the evolution of morbidly obese subjects after bariatric surgery remains unknown. In this prospective study we analyze the association between the improvement in the morbidly obese patients as a result of bariatric surgery and the basal expression of lipogenic and lipolytic genes.

Methods

We study 23 non diabetic morbidly obese patients who were studied before and 7 months after bariatric surgery. Also, we analyze the relative basal mRNA expression levels of lipogenic and lipolytic genes in epiploic visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT).

Results

When the basal acetyl-CoA carboxylase 1 (ACC1), acetyl-CoA synthetase 2 (ACSS2) and ATP citrate lyase (ACL) expression in SAT was below percentile-50, there was a greater decrease in weight (P = 0.006, P = 0.034, P = 0.026), body mass index (P = 0.008, P = 0.033, P = 0.034) and hip circumference (P = 0.033, P = 0.021, P = 0.083) after bariatric surgery. In VAT, when the basal ACSS2 expression was below percentile-50, there was a greater decrease in hip circumference (P = 0.006). After adjusting for confounding variables in logistic regression models, only the morbidly obese patients with SAT or VAT ACSS2 expression≥P50 before bariatric surgery had a lower percentage hip circumference loss (

Conclusions

A lower basal ACSS2, ACC1 and ACL expression, genes involved in de novo lipogenesis, is associated with a better evolution of anthropometric variables after bariatric surgery. Thus, the previous state of the pathways involved in fatty acid metabolism may have repercussions on the improvement of these patients.

doi:10.1371/journal.pone.0031280

PMCID: PMC3285616 PMID: 22384010

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9. Cyclin G2 regulates adipogenesis through PPARγ coactivation

Endocrinology 2010;151(11):5247-5254.

Summary

Cell cycle regulators such as cyclins, cyclin dependant kinases (CDKs) or Rb play important roles in the differentiation of adipocytes. In the present paper we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here, that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to PPARγ, the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARγ coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARγ-responsive element of the promoter of aP2, which is a PPARγ target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARγ. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis.

doi:10.1210/en.2010-0461

PMCID: PMC3000854 PMID: 20844002

3T3-L1 Cells; Adipocytes; cytology; metabolism; Adipogenesis; genetics; Animals; Cells, Cultured; Cyclin G2; genetics; metabolism; Fluorescent Antibody Technique; Immunoprecipitation; Male; Mice; Mice, Inbred C57BL; PPAR gamma; genetics; metabolism; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Up-Regulation; adipogenesis; cyclin G2; PPARγ

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10. Platelet count and Interleukin 6 Gene polymorphism in healthy subjects

Fernandez-Real, José-Manuel | Vendrell, Joan | Richart, Cristobal | Gutierrez, Cristina | Ricart, Wifredo

BMC Medical Genetics 2001;2:6.

Background

Interleukin 6 (IL-6) is thought to play important roles in the development of reactive thrombocytosis caused by inflammation by its stimulatory effect on megakaryocytopoiesis. A G/C polymorphism of the IL-6 gene at position -174 has been found to be associated to different transcription rates. Specifically, subjects with the CC genotype showed lower plasma IL-6 levels compared with GC or GG subjects. Given this difference in transcription rates of IL-6 we speculated on different platelet count according to this IL-6 polymorphism.

Methods

The G/C polymorphism of the IL-6 gene at position -174, serum IL-6 concentration and platelet count were prospectively analyzed in 59 (25 women) consecutive healthy subjects.

Results

Subjects who were homozygotes for the C allele at position -174 of the IL-6 gene (Sfa NI genotype) showed significantly lower platelet count than carriers of the G allele, despite similar age, sex, body mass index and proportion of smokers (205400 ± 44088 vs 239818 ± 60194, p = 0.047). This was in parallel to differences in peripheral white blood cell count (5807 ± 1671 vs 6867 ± 1192 × 109/ml, p = 0.01).

Conclusion

This is the first description, to our knowledge, of a genetical influence on basal platelet counts, which appears to be partially dependent on a polymorphism of the IL-6 gene, even in the absence of inflammation.

doi:10.1186/1471-2350-2-6

PMCID: PMC32250 PMID: 11397324

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