Xavi Escoté - Academia.edu (original) (raw)

Papers by Xavi Escoté

HIV Medicine, 2011

The aim of the study was to determine circulating levels of fatty acid binding protein 4 (FABP-4)... more 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. Methods A total of 282 HIV-1-infected patients treated with stable cART for at least 1 year (132 with lipodystrophy and 150 without) and 185 uninfected controls (UCs) were included in the study. Anthropometric parameters were determined. Plasma levels of FABP-4, soluble tumour necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2), interleukin-18 (IL-18), IL-6, adiponectin and leptin were also analysed. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous adipose tissue mRNA expression of proinflammatory cytokines was assessed in 38 patients (25 with lipodystrophy and 13 without) by real-time polymerase chain reaction (PCR). Results The plasma FABP-4 concentration was significantly higher in patients with lipodystrophy than in those without (P 5 0.012). FABP-4 concentration was positively correlated with body mass index (BMI), HOMA-IR, and the concentrations of insulin, total cholesterol, triglycerides, sTNF-R1, leptin and IL-18, but showed a negative correlation with high-density lipoprotein (HDL) cholesterol and adiponectin concentrations. After adjusting for age, sex and BMI, the odds ratio (OR) for risk of lipodystrophy was found to be significantly increased for those with the highest levels of FABP-4 [OR 0.838, 95% confidence interval (CI) 0.435-1.616 for medium FABP-4 vs. OR 2.281, 95% CI 1.163-4.475 for high FABP-4]. In a stepwise regression model, FABP-4 was independently associated with HOMA-IR after controlling for clinical and inflammatory parameters (P 5 0.004). Moreover, a positive relationship was observed in patients with lipodystrophy between subcutaneous adipose tissue CD68 expression and FABP-4 plasma levels (r 5 0.525; P 5 0.031).

The Journal of Clinical Endocrinology & Metabolism, 2009

Context: Zinc-α2-glycoprotein (ZAG) is a soluble protein similar to the class I major histocompat... more Context: Zinc-α2-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 PPARγ, 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 ...

International journal of molecular sciences, Jan 15, 2017

Adipose tissue releases bioactive mediators called adipokines. This review focuses on the effects... more Adipose tissue releases bioactive mediators called adipokines. This review focuses on the effects of omentin, vaspin, cardiotrophin-1, Tumor necrosis factor-like Weak Inducer of Apoptosis (TWEAK) and nephroblastoma overexpressed (NOV/CCN3) on obesity and diabetes. Omentin is produced by the stromal-vascular fraction of visceral adipose tissue. Obesity reduces omentin serum concentrations and adipose tissue secretion in adults and adolescents. This adipokine regulates insulin sensitivity, but its clinical relevance has to be confirmed. Vaspin is produced by visceral and subcutaneous adipose tissues. Vaspin levels are higher in obese subjects, as well as in subjects showing insulin resistance or type 2 diabetes. Cardiotrophin-1 is an adipokine with a similar structure as cytokines from interleukin-6 family. There is some controversy regarding the regulation of cardiotrophin-1 levels in obese -subjects, but gene expression levels of cardiotrophin-1 are down-regulated in white adipose t...

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, May 10, 2017

The beneficial actions of n-3 fatty acids on obesity-induced insulin resistance and inflammation ... more The beneficial actions of n-3 fatty acids on obesity-induced insulin resistance and inflammation have been related to the synthesis of specialized proresolving lipid mediators (SPMs) like resolvins. The aim of this study was to evaluate the ability of one of these SPMs, maresin 1 (MaR1), to reverse adipose tissue inflammation and/or insulin resistance in two models of obesity: diet-induced obese (DIO) mice and genetic (ob/ob) obese mice. In DIO mice, MaR1 (2 μg/kg; 10 d) reduced F4/80-positive cells and expression of the proinflammatory M1 macrophage phenotype marker Cd11c in white adipose tissue (WAT). Moreover, MaR1 decreased Mcp-1, Tnf-α, and Il-1β expression, while upregulated adiponectin and Glut-4 and increased Akt phosphorylation in WAT. MaR1 administration (2 μg/kg; 20 d) to ob/ob mice did not modify macrophage recruitment but increased the M2 macrophage markers Cd163 and Il-10. MaR1 reduced Mcp-1, Tnf-α, Il-1β, and Dpp-4 and increased adiponectin gene expression in WAT. MaR...

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Apr 17, 2017

Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we an... more Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects. The circadian rhythmicity of oxygen consumption rate (Vo2) was disrupted in aged-obese CT-1-deficient (CT-1(-/-)) mice (12 mo). Although circadian rhythms of Vo2 were conserved in young-lean CT-1(-/-) mice (2 mo), CT-1 deficiency caused a phase shift of the acrophase. Most of the clock genes studied (Clock, Bmal1, and Per2) displayed a circadian rhythm in adipose tissue of both wild-type (WT) and CT-1(-/-) mice. However, the pattern was altered in CT-1(-/-) mice toward a lower percentage of the rhythm or lower amplitude, especially for Bmal1 and Clock. Moreover, CT-1 mRNA levels in adipose tissue showed significant circadian fluctuations in young WT mice. In human...

Endocrinología, Diabetes y Nutrición, 2017

Cushing syndrome (CS), an endogenous hypercortisolemic condition with increased cardiometabolic m... more Cushing syndrome (CS), an endogenous hypercortisolemic condition with increased cardiometabolic morbidity, leads to development of abdominal obesity, insulin resistance, diabetes and proatherogenic dyslipidemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized lipolytic adipokine implicated in regulation of adipose tissue metabolism and fat distribution. In vitro and animal studies suggest that glucocorticoids interact with ZAG secretion and action. To assess the relationship between ZAG and glucocorticoids in a human model of hypercortisolism, circulating ZAG levels were tested in patients with CS and its counterpart controls. An observational, cross-sectional study on 39 women, 13 with active CS and 26 controls matched by age and body mass index. Plasma ZAG levels (μg/ml) were measured by ELISA and correlated with hypercortisolism, metabolic, and phenotypic parameters. Plasma ZAG levels were significantly higher in patients with CS compared to controls (64.3±16.6 vs. 44.0±16.1, p=0.002). In a univariate analysis, ZAG levels positively correlated to 24-h urinary free cortisol (p=0.001), body mass index (p=0.02), non-esterified fatty acids (p=0.05), glucose (p=0.003), LDL-C (p=0.028), and type 2 diabetes mellitus (p=0.016), and were inversely related to total adiponectin levels (p=0.035). In a multivariate analysis, after adjusting for CS, ZAG levels only correlated with body mass index (p=0.012), type 2 diabetes mellitus (p=0.004), and glucose (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). This study provides initial evidence that plasma ZAG levels are higher in patients with CS as compared to controls. The close relationship of ZAG with metabolic and phenotypic changes in CS suggests that ZAG may play a significant role in adipose tissue changes in hypercortisolism.

BioFactors, 2016

In obesity, the increment of adiposity levels disrupts the whole body homeostasis, promoting an o... more In obesity, the increment of adiposity levels disrupts the whole body homeostasis, promoting an over production of oxidants and inflammatory mediators. The current study aimed to characterize the transcriptomic changes promoted by supplementation with eicosapentaenoic acid (EPA, 1.3 g/day), α-lipoic acid (0.3 g/day), or both (EPA + α-lipoic acid, 1.3 g/day + 0.3 g/day) in subcutaneous abdominal adipose tissue from overweight/obese healthy women, who followed a hypocaloric diet (30% of total energy expenditure) during ten weeks, by using a microarray approach. At the end of the intervention, a total of 33,297 genes were analyzed using Affymetrix GeneChip arrays. EPA promoted changes in extracellular matrix remodeling gene expression, besides a rise of genes associated with either chemotaxis or wound repair. α-Lipoic acid decreased expression of genes related with cell adhesion and inflammation. Furthermore, α-lipoic acid, especially in combination with EPA, upregulated the expression of genes associated with lipid catabolism while downregulated genes involved in lipids storage. Together, all these data suggest that some of the metabolic effects of EPA and α-lipoic acid could be related to their regulatory actions on adipose tissue metabolism. © 2016 BioFactors, 2016.

Diabetologia, 2015

Aims/hypothesis Lipopolysaccharide (LPS) binding protein (LBP) is a novel 65 kDa adipokine, linke... more Aims/hypothesis Lipopolysaccharide (LPS) binding protein (LBP) is a novel 65 kDa adipokine, linked to adipose tissue (AT) inflammation, obesity and insulin resistance, that inhibits adipocyte differentiation. Here, we investigated the molecular mechanisms behind these detrimental effects on adipogenesis through whole-genome transcriptomics and in vitro experiments. Methods Permanent and transient knockdown (KD) and coculture experiments were performed in 3T3-L1 and 3T3-F442A cell lines during adipocyte differentiation. Microarray gene expression was performed using Genechip Affymetrix technology and validated by real-time PCR. Results LBP KD of 3T3-L1 cells led to a potentiated adipocyte differentiation with a dose-response relationship; genes involved in mitochondrial biogenesis, fatty acid metabolism and peroxisome proliferator-activated receptor γ (PPAR-γ) action were dramatically upregulated in parallel to increased insulin signalling. Cells with LBP KD became refractory to proinflammatory cytokines and other inflammatory stimuli (LPS and palmitate). This phenotype, mediated through disrupted nuclear factor κB (NFκB) signalling, was reversed by a soluble factor present in a co-culture with native cells and by exogenous LBP. Double-silencing of LBP and toll-like receptor 4 (TLR4) again rendered these cells insensitive to co-culture, LBP and inflammatory factors. Conclusions/interpretation In summary, LBP is a proinflammatory soluble adipokine that acts as a brake for adipogenesis, strengthening the negative effects of palmitate and LPS on adipocyte differentiation.

American Journal of Physiology - Endocrinology And Metabolism, 2015

Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammat... more Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammation, macrophage infiltration, and decreased fatty acid oxidation (FAO). Here, we report that the expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in mitochondrial FAO, is higher in human adipose tissue macrophages than in adipocytes and that it is differentially expressed in visceral vs. subcutaneous adipose tissue in both an obese and a type 2 diabetes cohort. These observations led us to further investigate the potential role of CPT1A in adipocytes and macrophages. We expressed CPT1AM, a permanently active mutant form of CPT1A, in 3T3-L1 CARΔ1 adipocytes and RAW 264.7 macrophages through adenoviral infection. Enhanced FAO in palmitate-incubated adipocytes and macrophages reduced triglyceride content and inflammation, improved insulin sensitivity in adipocytes, and reduced endoplasmic reticulum stress and ROS damage in macrophages. We conclude that incre...

Journal of Cell Science & Therapy, 2014

Lee and colleagues have shown that CDK4 plays a central role in glucose homeostasis. Insulin acti... more Lee and colleagues have shown that CDK4 plays a central role in glucose homeostasis. Insulin activates cyclin D1-CDK4, leading to a decrease in circulating glucose as a consequence of the down-regulation of main genes involved in liver gluconeogenesis. Commentary In recent years, our knowledge of CDK regulation has improved significantly and is no longer restricted to just its role in the control of cell cycle progression. Cyclin-dependent kinases (CDKs) are serine/ threonine protein kinases that are associated with their specific partners, cyclins which phosphorylate their protein targets. Thus, the cyclin-CDK complex works as a holoenzyme. The control of cell cycle progression by cyclin-CDK complexes was first studied several years ago, in the context of high proliferation rates and cancer. Understanding how CDKs function was one of the main aims of these studies, as the loss of this regulation can alter cell proliferation rates which, in the worst case scenario, may translate into malignant tumours.

MAP Kinase, 2013

Eukaryotic cells coordinate various intracellular activities in response to environmental stresse... more Eukaryotic cells coordinate various intracellular activities in response to environmental stresses, activating an adaptive program to maximize the probability of survival and proliferation. Cells transduce diverse cellular stimuli by multiple mitogen-activated protein kinase (MAPK) cascades. MAPK are key signal transduction kinases required to respond to stress. A prototypical member of the MAPK family is the yeast high osmolarity glycerol (Hog1). Activation of Hog1 results in the generation of a set of adaptive responses that leads to the modulation of several aspects of cell physiology that are essential for cell survival, such as gene expression, translation, and morphogenesis. This review focuses on the control of cell cycle progression by Hog1 which is critical for cell survival in response to stress conditions.

The EMBO Journal, 2006

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for ce... more Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. Exposure of yeast to osmostress leads to activation of the Hog1 SAPK, which controls cell cycle at G 1 by the targeting of Sic1. Here, we show that survival to osmostress also requires regulation of G 2 progression. Activated Hog1 interacts and directly phosphorylates a residue within the Hsl7-docking site of the Hsl1 checkpoint kinase, which results in delocalization of Hsl7 from the septin ring and leads to Swe1 accumulation. Upon Hog1 activation, cells containing a nonphosphorylatable Hsl1 by Hog1 are unable to promote Hsl7 delocalization, fail to arrest at G 2 and become sensitive to osmostress. Together, we present a novel mechanism that regulates the Hsl1-Hsl7 complex to integrate stress signals to mediate cell cycle arrest and, demonstrate that a single MAPK coordinately modulates different cell cycle checkpoints to improve cell survival upon stress.

PLoS ONE, 2012

Objective: Zinc-a 2 glycoprotein (ZAG) stimulates lipid loss by adipocytes and may be involved in... more Objective: Zinc-a 2 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 PPARc, 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.

PLoS ONE, 2014

Context: The Activin A-Follistatin system has emerged as an important regulator of lipid and gluc... more Context: The Activin A-Follistatin system has emerged as an important regulator of lipid and glucose metabolism with possible repercussions on fetal growth. Objective: To analyze circulating activin A, follistatin and follistatin-like-3 (FSTL3) levels and their relationship with glucose metabolism in pregnant women and their influence on fetal growth and neonatal adiposity. Design and methods: A prospective cohort was studied comprising 207 pregnant women, 129 with normal glucose tolerance (NGT) and 78 with gestational diabetes mellitus (GDM) and their offspring. Activin A, follistatin and FSTL3 levels were measured in maternal serum collected in the early third trimester of pregnancy. Serial fetal ultrasounds were performed during the third trimester to evaluate fetal growth. Neonatal anthropometry was measured to assess neonatal adiposity. Results: Serum follistatin levels were significantly lower in GDM than in NGT pregnant women (8.2162.32 ng/mL vs 9.2263.41, P = 0.012) whereas serum FSTL3 and activin A levels were comparable between the two groups. Serum follistatin concentrations were negatively correlated with HOMA-IR and positively with ultrasound growth parameters such as fractional thigh volume estimation in the middle of the third trimester and percent fat mass at birth. Also, in the stepwise multiple linear regression analysis serum follistatin levels were negatively associated with HOMA-IR (b = 20.199, P = 0.008) and the diagnosis of gestational diabetes (b = 20.138, P = 0.049). Likewise, fractional thigh volume estimation in the middle of third trimester and percent fat mass at birth were positively determined by serum follistatin levels (b = 0.214, P = 0.005 and b = 0.231, P = 0.002, respectively). Conclusions: Circulating follistatin levels are reduced in GDM compared with NGT pregnant women and they are positively associated with fetal growth and neonatal adiposity. These data suggest a role of the Activin-Follistatin system in maternal and fetal metabolism during pregnancy.