Merce Miranda

Circulating and Adipose Tissue Gene Expression of Zinc-α2-Glycoprotein in Obesity: Its Relationship with Adipokine and Lipolytic Gene Markers in Subcutaneous and Visceral Fat

CONTEXT Zinc-alpha2-glycoprotein (ZAG) is a soluble protein similar to the class I major histocompatibility complex heavy chain, which has been implicated in lipid catabolism. We hypothesized that ZAG mRNA expression in adipose tissue may be linked with lipolytic and adipokine gene expression and have a close relationship with clinical phenotype. OBJECTIVES The objective of the study was to analyze ZAG gene expression in human adipose tissue from lean and obese subjects. ZAG circulating plasma levels and its relationship with cardiometabolic risk factors were also studied. DESIGN Seventy-three Caucasian (43 male and 30 female) subjects were included. Plasma and adipose tissue [sc (SAT) and visceral (VAT)] from the same patient were studied. mRNA of PPARgamma, hormone-sensitive lipase (HSL), adipose triglyceride lipase, adiponectin, omentin, visfatin, and ZAG were quantified. Plasma concentrations of ZAG were determined with ELISA. RESULTS ZAG plasma levels showed a negative correlation with insulin (r = -0.39; P = 0.008) and the homeostasis model assessment for insulin resistance index (r = -0.36; P = 0.016). No differences in ZAG circulating levels according to body mass index classification were observed. ZAG expression in SAT was significantly reduced in overweight and obese individuals compared with lean subjects (P < 0.001 and P = 0.007, respectively). ZAG mRNA expression in both SAT and VAT depots were negatively correlated with many clinical and metabolic cardiovascular risk factors. After multiple linear regression analysis, SAT ZAG was mainly predicted by adiponectin mRNA expression (B = 0.993; P < 0.0001) and plasma triglyceride levels (B = -0.565; P = 0.006). VAT ZAG expression was predicted by adiponectin expression (B = 0.449; P < 0.0001), and HSL VAT expression (B = 0.180; P = 0.023). CONCLUSIONS The present study provides evidence of a role of ZAG gene in adipose tissue metabolism, with a close association with adiponectin gene expression in sc and visceral fat.

Monocyte chemoattractant protein-1 in obesity and type 2 diabetes. Insulin sensitivity study.

Objective: Our goal was to test any association between human plasma circulating levels of monocyte chemoattractant protein‐1 (cMCP‐1) and insulin resistance and to compare monocyte chemoattractant protein‐1 (MCP‐1) adipose tissue gene expression and cMCP‐1 in relation with inflammatory markers.

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

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.

Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro.

Objective:To investigate fetal antigen 1 (FA1) protein within the context of human obesity and its relation with insulin sensitivity.Subjects:Cross-sectional study that analyses circulating levels of FA1 in two selected human cohorts: n=127 men for the study of FA1 circulating levels in the context of obesity and insulin sensitivity (Si); and n=61 severely obese women before and after bariatric surgery. The response in vitro to FA1 protein on human cell lines of monocytes, preadipocytes and mature adipocytes was studied.Measurements:Anthropometrical parameters: body mass index, waist-to-hip ratio, waist circumference, fat-free mass and fat mass. Clinical parameters: lipid profile (high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides), glycemic profile (fasting glucose, insulin, Si, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance), cytokines (sIL-6), adipokines (adiponectin) and circulating soluble fractions of tumor necrosis factor-α receptors 1 and 2 (sTNFR1 and sTNFR2).Results:In the obesity study, levels of FA1 in serum were found to increase with obesity. The Si index was negatively dependent on FA1 levels. In severe obesity, serum levels of FA1 decreased 1.4-fold 6 months after bariatric surgery. In vitro assays with FA1 protein on human monocytes and adipocytes cell lines modified the expression of pro-inflammatory cytokines and adipokines (tumor necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1), IL-6 (interleukin-6) and adiponectin).Conclusion:FA1 serum levels were increased in obese subjects and might influence Si. The stimulatory effect of FA1 protein on pro-inflammatory cytokines on both immune and adipose cell types could contribute to worsening the inflammatory environment observed in obesity.

Distinct roles of the phosphatidate phosphatases lipin 1 and 2 during adipogenesis and lipid droplet biogenesis in 3T3-L1 cells.

Background: Lipins are phosphatidate phosphatases that generate diacylglycerol for lipid synthesis. Results: Lipin 1 or lipin 2 depletion has distinct effects on differentiating adipocytes. Cells depleted of both lipins after initiation of adipogenesis accumulate triacylglycerol but display lipid droplet fragmentation. Conclusion: Lipins have a role in lipid droplet biogenesis after initiation of adipogenesis. Significance: Lipins play multiple roles during adipocyte differentiation. Lipins are evolutionarily conserved Mg2+-dependent phosphatidate phosphatase (PAP) enzymes with essential roles in lipid biosynthesis. Mammals express three paralogues: lipins 1, 2, and 3. Loss of lipin 1 in mice inhibits adipogenesis at an early stage of differentiation and results in a lipodystrophic phenotype. The role of lipins at later stages of adipogenesis, when cells initiate the formation of lipid droplets, is less well characterized. We found that depletion of lipin 1, after the initiation of differentiation in 3T3-L1 cells but before the loading of lipid droplets with triacylglycerol, results in a reciprocal increase of lipin 2, but not lipin 3. We generated 3T3-L1 cells where total lipin protein and PAP activity levels are down-regulated by the combined depletion of lipins 1 and 2 at day 4 of differentiation. These cells still accumulated triacylglycerol but displayed a striking fragmentation of lipid droplets without significantly affecting their total volume per cell. This was due to the lack of the PAP activity of lipin 1 in adipocytes after day 4 of differentiation, whereas depletion of lipin 2 led to an increase of lipid droplet volume per cell. We propose that in addition to their roles during early adipogenesis, lipins also have a role in lipid droplet biogenesis.

The IL-6 system in HIV-1-infection and in HAART-related fat redistribution syndromes.

We determined the IL-6 −174 G>C single nucleotide polymorphism, IL-6 mRNA expression in subcutaneous adipose tissue (SAT) and IL-6 plasma levels in HIV-1-infected patients with and without lipodystrophy and uninfected controls. HIV-1-infected patients had a greater prevalence of the IL-6 −174 C/C genotype and the C allele, higher SAT IL-6 mRNA expression and plasma IL-6 levels than controls. The IL-6 −174 G>C genotype distribution and allele frequencies, SAT IL-6 mRNA expression and IL-6 plasma levels were non-significantly different between HIV-1-infected patients with and without lipodystrophy.

Lipodystrophy and Insulin Resistance in Combination Antiretroviral Treated HIV-1―Infected Patients: Implication of Resistin

Background:Little information is available with respect to the involvement of resistin in lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with combination antiretroviral therapy (cART). We determined whether the resistin (rest) −420C>G single-nucleotide polymorphism and plasma resistin are associated with the development of lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with cART. Methods:The study group comprised 299 HIV-1-infected patients treated with a stable cART for at least 1 year (143 with lipodystrophy and 156 without) and 175 uninfected controls. Anthropometric, clinical, and metabolic variables were determined. Homeostasis model assessment for insulin resistance was used to evaluate insulin resistance. Plasma resistin levels were determined by enzyme-linked immunosorbent assay. The rest −420C>G was assessed using restriction fragment length polymorphism. Student t test, 1-way and 2-way analysis of variance, χ2 test, and Pearson and Spearman correlations were performed for statistical analysis. Results:Genotypes containing the rest −420G variant allele were significantly more common in HIV-1-infected patients without lipodystrophy compared with those with lipodystrophy (P = 0.037). Infected patients had significantly greater plasma resistin levels than uninfected controls (P < 0.001). Among infected patients, plasma resistin levels were significantly lower in patients with lipodystrophy with respect to those without (P = 0.034). In infected patients, plasma resistin levels had a significant positive correlation with insulin and homeostasis model assessment for insulin resistance: P < 0.001 and P = 0.002 in the lipodystrophy subset and P = 0.002 and P = 0.03 in the nonlipodystrophy subset, respectively. Conclusions:In our cohort of white Spaniards, the rest −420C>G single-nucleotide polymorphism may be associated with cART-related lipodystrophy. Plasma resistin correlates with insulin resistance in infected patients with and without lipodystrophy.

Relation between human LPIN1, hypoxia and endoplasmic reticulum stress genes in subcutaneous and visceral adipose tissue.

Context:LPIN1 is the phosphatidic acid phosphatase that produces 1,2-diacylglycerol, and thus it is related to the synthesis of triglycerides in the adipocyte. LPIN1 has a role in lipid synthesis and nuclear receptor coactivation, both of which may be involved in lipid homeostasis and metabolism. Among others, hypoxia and endoplasmic reticulum (ER) stress are being shown to be related to the adipose dysfunction found in human obesity.Objective:The aim of this study was to analyze LPIN1 gene expression in human adipose tissue in parallel with several hypoxia, angiogenic, ER stress and peroxisome proliferator-activated receptor (PPAR)-related genes in human obesity.Design and Patients:Gene expression was quantified in abdominal (subcutaneous and visceral) adipose tissue from 62 subjects.Results:We have shown a marked association between LPIN1 and PPARα gene expression both in subcutaneous and visceral adipose tissues. Similarly, a strong interdependence with vascular endothelial growth factor (VEGF) gene expression was also described; in fact, LPIN1 and VEGF expression levels were significantly decreased with obesity to a similar extent.Conclusion:These associations might suggest a possible role of LPIN1 in stress conditions that occur in chronic obesity and underlie insulin resistance.

A study of fatty acid binding protein 4 in HIV‐1 infection and in combination antiretroviral therapy‐related metabolic disturbances and lipodystrophy

The aim of the study was to determine circulating levels of fatty acid binding protein 4 (FABP‐4) in a cohort of HIV‐1‐infected patients treated with combination antiretroviral therapy (cART) and to investigate the relationships between FABP‐4 levels and insulin resistance, dyslipidaemia, lipodystrophy and levels of proinflammatory adipocytokines in these patients.

The stress-activated protein kinase Hog1 develops a critical role after resting state

Quiescence is an essential process in eukaryotes. Control of cell cycle progression by stress‐activated protein kinases (SAPK) is critical for cell adaptation to extracellular stimuli. In yeast, activation of the HOG MAPK signalling pathway results in the control of cell cycle at several phases. In this manuscript, we describe the role of Hog1p modulating re‐entry into cell cycle from a resting state. Cells deficient in Hog1p activation show a delay in entering the mitotic cell cycle from the stationary phase. Furthermore, a repressible Hog1p allele (Hog1AS) presents a comparable behaviour at this phase to the deleted strain. In addition, the role of Hog1p at the stationary phase exit is not related to loss of cell viability. Moreover, when cells enter the mitotic cell cycle after being in the stationary phase, Hog1p is rapidly activated and concentrates in the nucleus where it modifies the expression of several genes. Similar results are obtained in higher eukaryotic cells by activation of p38. Thus, these results reveal a novel role of the SAPK Hog1p in the control of cell cycle progression as cells leave a resting state.