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New research presented at this year's European Congress on Obesity (ECO) in Porto, Portugal (17-20 May) shows the obese people have higher levels of a protein called survivin, which protects fat-containing adipocyte cells in the body from being destroyed. The study was led by Dr Sonia Fernández-Veledo and Dr Joan Vendrell and is presented at ECO by Dr Miriam Ejarque, all of the Pere Virgili Institute, Rovira i Virgili University, CIBERDEM, Taragona, Spain. Adipose tissue (AT) has a central role in obesity-related metabolic imbalance through the dysregulated production of inflammatory proteins called cytokines and adipokines. In addition to its known risk for cardiovascular disease and diabetes, obesity is also a major risk for cancer. Human adipocyte-derived stem cells (hASCs), which determine AT expansion, are important players in pathological development of obesity and associated cancer; however, the mechanisms underlying hASCs-induced alterations in cancer remain unknown. The authors aimed to better understand these mechanisms. hASCs were isolated from subcutaneous AT of lean and obese subjects. Serum and AT from a cross-sectional study of 111 subjects classified by body-mass index were collected. Apoptosis (the process of cell death) was measured by flow cytometry, which uses highly focused beams of light to analyse functioning of individual cells. Gene and protein expression were assessed using the standard methods of quantitative polymerase chain reaction (qPCR) and western blotting. The authors then investigated the impact of obesity on the expression of survivin, an anti-apoptotic protein (which protects cells from death), already known to be a diagnostic biomarker of tumour onset and recurrence that has been studied in several cancers. In this new cross-sectional study, circulating levels of survivin and gene expression in subcutaneous AT were 2.5 times higher in obese and morbidly obese patients than lean patients. Within AT, survivin was detected in hASCs, and its expression was significantly increased in obesity and by pro-inflammatory interleukin proteins. Analysis of survivin expression in hASCs revealed a complex regulation within cell mechanisms, including epigenetic modifications and improved protein stability (giving the cell protection). "We discovered that survivin levels determine the susceptibility of hASCs to stimuli that cause the cell to die," explains Dr Ejarque Carbó. "hASCs from an obese person were better protected from death than those in normal weight subjects." She concludes: "Collectively, these data shed new light on the molecular mechanisms controlling AT expansion in obesity through promotion of hASCs that are resistant to cell death, and point to survivin as a new molecular player in the communication between hASCs and tumour cells. Thus, promoting cell death by targeting survivin might represent an effective strategy for both obesity and cancer therapy."


Pizarro-Delgado J.,Complutense University of Madrid | Fasciani I.,Ramon y Cajal Hospital IRYCIS | Temperan A.,Ramon y Cajal Hospital IRYCIS | Romero M.,Ramon y Cajal Hospital IRYCIS | And 16 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2014

The existence of functional connexin36 (Cx36) hemichannels in β-cells was investigated in pancreatic islets of rat and wild-type (Cx36+/+), monoallelic (Cx36+/-), and biallelic (Cx36-/-) knockout mice. Hemichannel opening by KCl depolarization was studied by measuring ATP release and changes of intracellular ATP (ADP). Cx36+/+ islets lost ATP after depolarization with 70 mM KCl at 5 mM glucose; ATP loss was prevented by 8 and 20 mM glucose or 50 μM mefloquine (connexin inhibitor). ATP content was higher in Cx36-/- than Cx36+/+ islets and was not decreased by KCl depolarization; Cx36+/- islets showed values between that of control and homozygous isletFive minimolar extracellular ATP increased ATP content and ATP/ADP ratio and induced a biphasic insulin secretion in depolarized Cx36+/+ and Cx36+/- but not Cx36-/- islets. Cx36 hemichannels expressed in oocytes opened upon depolarization of membrane potential, and their activation was inhibited by mefloquine and glucose (IC50 ~8 mM). It is postulated that glucose-induced inhibition of Cx36 hemichannels in islet β-cells might avoid depolarization-induced ATP loss, allowing an optimum increase of the ATP/ADP ratio by sugar metabolism and a biphasic stimulation of insulin secretion. Gradual suppression of glucose-induced insulin release in Cx36+/- and Cx36-/- islets confirms that Cx36 gap junction channels are necessary for a full secretory stimulation and might account for the glucose intolerance observed in mice with defective Cx36 expression. Mefloquine targeting of Cx36 on both gap junctions and hemichannels also suppresses glucose-stimulated secretion. By contrast, glucose stimulation of insulin secretion requires Cx36 hemichannels' closure but keeping gap junction channels opened. © 2014 the American Physiological Society.


Soriguer F.,Hospital Regional Universitario Carlos Haya | Valdes S.,Hospital Regional Universitario Carlos Haya | Morcillo S.,Fundacion IMABIS | Esteva I.,Hospital Regional Universitario Carlos Haya | And 12 more authors.
European Journal of Clinical Investigation | Year: 2011

Background Different studies, mostly cross-sectional, have found an association between low levels of thyroid hormones, even within the normal range, and a greater body mass index. The aim of this study was to determine the association between thyroid function and the risk for obesity. Materials and methods In this population-based prospective study, measurements were made of anthropometric parameters, thyroid hormone function and urinary iodine in a cohort of the Pizarra Study (n=937), and repeated 6years later (n=784). At the second point, measurements were also made of leptin and adiponectin. Results Among the persons who were not obese at the start of the study, the odds ratio (OR) of becoming obese for those in the fourth quartile (Q 4) for free triiodothyronine (FT3) (versus those in Q 1) was 2·94 (1·46-5·90) (P=0·005). The OR of becoming obese in persons in Q 4 of FT4 (versus those in Q 1) was 3·06 (1·23-7·43) (P=0·01). Those persons in Q 4 of weight gain had a higher FT3 at the 6-year follow-up than those whose weight gain was in Q 1 (P<0·001). Leptin correlated with thyrotropin (β=0·58, P=0·001) and the FT4 (β=-1·12, P=0·005). Adiponectin correlated with FT3 (r=-0·24, P<0·001). The urinary iodine correlated negatively with both the BMI (β=-0·08, P=0·01) and the increase in weight (β=-0·08, P=0·04). Conclusions The changes in the thyroid hormones could be the consequence, rather than the cause, of the increase in weight. The same pathophysiological mechanisms that induce obesity might also be modifying the thyroid hormone pattern. © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.


Hernandez C.,Autonomous University of Barcelona | Garcia-Ramirez M.,Autonomous University of Barcelona | Corraliza L.,Autonomous University of Barcelona | Fernandez-Carneado J.,BCN Peptides | And 7 more authors.
Diabetes | Year: 2013

Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Somatostatin (SST) is an endogenous neuroprotective peptide that is downregulated in the diabetic eye. The aim of the study was to test the usefulness of topical administration of SST in preventing retinal neurodegeneration. For this purpose, rats with streptozotocin-induced diabetes mellitus (STZ-DM) were treated with either SST eye drops or vehicle for 15 days. Nondiabetic rats treated with vehicle served as a control group. Functional abnormalities were assessed by electroretinography (ERG), and neurodegeneration was assessed by measuring glial activation and the apoptotic rate. In addition, proapoptotic (FasL, Bid, and activation of caspase-8 and caspase-3) and survival signaling pathways (BclxL) were examined. Intraretinal concentrations of glutamate and its main transporter glutamate/aspartate transporter (GLAST) were also determined. Treatment with SST eye drops prevented ERG abnormalities, glial activation, apoptosis, and the misbalance between proapoptotic and survival signaling detected in STZ-DM rats. In addition, SST eye drops inhibited glutamate accumulation in the retina and GLAST downregulation induced by diabetes mellitus. We conclude that topical administration of SST has a potent effect in preventing retinal neurodegeneration induced by diabetes mellitus. In addition, our findings open up a new preventive pharmacological strategy targeted to early stages of DR. © 2013 by the American Diabetes Association.


News Article | February 23, 2017
Site: www.eurekalert.org

Is a tool that makes it possible to monitor metabolic fluxes and, in 10 minutes, provide dynamic information about a considerable number of molecules. It may be able to be used in future applications to understand the reasons why some diseases develop If we were to take photographs at the underground stations in Barcelona, we would see the number of people waiting, find out what time the rush hour takes place and deduce why some stations are busier than others. We would not know, however, if something has happened between one station and another that has led to more people being on the platforms or that might have caused delays. This is what happens when the metabolism of a cell is studied. The metabolism of a cell is like an underground network in which the chemical structures of the metabolites go from one station to another by means of biochemical transformations. Up until now, it has been possible to determine the number of many metabolites in a cell, tissue or organism, but studying their fluxes is technically much more complex and time consuming. Now, however, a group of researchers from the URV, CIBERDEM and IRB Barcelona have developed a new tool that makes this possible. The nuclear magnetic resonance (NMR) techniques used to date covered very few metabolites, researchers could take hours to measure every sample and the data were difficult to interpret. The new approach is very quick - 10 minutes per sample -, many more metabolites are obtained and the results are much easier to interpret. That is to say, the movements made by the metabolism can be determined much more easily and effectively. It is a methodology based on NMR which measures hydrogen atoms (protons) in order to indirectly determine the number of carbon atoms that are marked in the chemical structures of the metabolites. The experiment is as follows: a nutrient is marked that the cells feed on, like glucose or aminoacids, with a stable isotope. Stable isotopes such as carbon 13 are not radioactive and do not represent any danger to organisms or the people who handle the samples. The proton is measured by NMR much more quickly and sensitively than the carbon and, in this way, it is possible to study the fluxes and the transformation dynamics of these nutrients inside the cell. So far the efficacy of this new technique has been validated using human cancer cells but it is directly applicable to any biological model. Diabetes, for example, is a metabolic syndrome in which the process begins long before the levels of glucose in the blood increase, because the body uses a variety of mechanisms to ensure that the concentration of this nutrient remains stable. And high levels of glucose are only seen in the blood when the disease is at an advanced stage. The technique that has just been reported describes a new way of studying the mechanisms that cause some tissues in the organism (for example, liver or pancreas cells) not to be able to regulate levels of glucose or to become insensitive to it. That is to say, the study of metabolic fluxes helps us understand the reasons why the disease develops and the mechanism by which it does so. Therefore, it also helps in the process of diagnosis. In short, it is a methodology with great potential that practising physicians and molecular biologists will be able to use to acquire greater understanding of certain diseases. The new technique, unlike more traditional techniques, does not use radioactivity to study the metabolism. The article, which has been published in the scientific journal Angewandte Chemie, shows the results of this work on cancer cells, but the researchers are sure that glucose, aminoacids and fats marked with stable isotopes can be found in other cells and even animals. The fact that they are not radioactive makes them much easier to work with because there is no need for special laboratory conditions. In their work, the researchers have used NMR quite differently from how it has traditionally been used to study the metabolism. Maria Vinaixa, a researcher from the URV's Department of Electronic Engineering and currently carrying out research at the University of Manchester, and Oscar Yanes, a researcher from the same URV department and coordinator of the Metabolomic Platform of the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), explain that with this methodology "we exploit to the full the power of nuclear magnetic resonance in terms of its sensitivity and coverage of the metabolism," and they believe that "it is difficult to take it any further". Now the limitation is the resonance itself. Vinaixa, M., Rodríguez, M. A., Aivio, S., Capellades, J., Gomez, J., Canyellas, N., Stracker, T. H. and Yanes, O. (2017), "Positional Enrichment by Proton Analysis (PEPA): A One-Dimensional 1H-NMR Approach for 13C Stable Isotope Tracer Studies in Metabolomics". Angew. Chem. Int. Ed. doi:10.1002/anie.201611347


Mallol R.,Rovira i Virgili University | Rodriguez M.A.,Rovira i Virgili University | Heras M.,CIBERDEM | Heras M.,Rovira i Virgili University | And 7 more authors.
Analytical and Bioanalytical Chemistry | Year: 2012

The sizes of certain types of lipoprotein particles have been associated with an increased risk of cardiovascular disease. However, there is currently no gold standard technique for the determination of this parameter. Here, we propose an analytical procedure to measure lipoprotein particles sizes using diffusion-ordered nuclear magnetic resonance spectroscopy (DOSY). The method was tested on six lipoprotein fractions, VLDL, IDL, LDL 1, LDL 2, HDL 2, and HDL 3, which were obtained by sequential ultracentrifugation from four patients. We performed a pulsed-field gradient experiment on each fraction to obtain a mean diffusion coefficient, and then determined the apparent hydrodynamic radius using the Stokes-Einstein equation. To validate the hydrodynamic radii obtained, the particle size distribution of these lipoprotein fractions was also measured using transmission electron microscopy (TEM). The standard errors of duplicate measurements of diffusion coefficient ranged from 0.5% to 1.3%, confirming the repeatability of the technique. The coefficient of determination between the hydrodynamic radii and the TEM-derived mean particle size was r 2∈=∈0.96, and the agreement between the two techniques was 85%. Thus, DOSY experiments have proved to be accurate and reliable for estimating lipoprotein particle sizes. [Figure not available: see fulltext.] © 2012 Springer-Verlag.


Mallol R.,Rovira i Virgili University | Rodriguez M.A.,Rovira i Virgili University | Brezmes J.,Rovira i Virgili University | Masana L.,CIBERDEM | And 2 more authors.
Progress in Nuclear Magnetic Resonance Spectroscopy | Year: 2013

NMR spectroscopy is the only technique that allows a full lipoprotein subfraction analysis of serum/plasma samples. The calibration and validation procedures used to set up new NMR methods rely on the correlations made between the NMR spectra and the lipids measured in a particular set of subfractions, all isolated by ultracentrifugation. Diffusion NMR spectroscopy can provide a direct measure of lipoprotein radii by using the diffusion coefficient and applying the Einstein Stokes equation. Nevertheless, the determination of the serum/plasma viscosity parameter in the formula is not straightforward. Many studies use NMR spectroscopy to characterize diabetic dyslipidemias. The number and size of the particles in the lipoprotein fractions provided by this technique have played an essential role in obtaining insight into this complex metabolic disease. Each NMR spectrum from a serum/plasma sample contains a wealth of information about lipoproteins.


Lazaro I.,Rovira i Virgili University | Diaz M.,CIBERDEM | Diaz M.,University of Barcelona | Cabre A.,Rovira i Virgili University | And 3 more authors.
Gynecological Endocrinology | Year: 2011

Objective.To assess the usefulness of circulating fatty acid-binding protein 4 (FABP4) as a predictive marker of long-term therapeutic outcome in girls with ovarian androgen excess and a history of precocious pubarche (PP) and low birth weight (LBW) and in young women with polycystic ovary syndrome (PCOS). Methods.We included 97 patients. Thirty-nine had a history of LBW-PP and were randomized to remain untreated (n=13) or to receive metformin (n=26). PCOS women (n=58) received low-dose flutamide-metformin plus an oral contraceptive. Auxology, androgens, glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR), lipid profile, FABP4, and body composition (by dual-energy X-ray absorptiometry) were assessed at baseline and after 2 years. Results.At baseline, FABP4 was associated with anthropometric measurements and fat body mass (all P<0.05). FABP4 levels increased less after follow-up in the PP-treated girls (P<0.05); in the PCOS patients, basal FABP4 levels were inversely associated with changes in systolic blood pressure, HOMA-IR, and total fat mass (all P<0.05). Body mass index-standard deviation scores was the main independent predictor of FABP4 variations (33%, P<0.001). Conclusion.FABP4 is a strong clinical biomarker of adiposity, IR, and the presence of the components of the metabolic syndrome in non-obese hyperandrogenic girls and young women; pretreatment FABP4 levels appear to predict therapeutic long-term response. © 2011 Informa UK, Ltd.


News Article | February 24, 2017
Site: phys.org

The metabolism of a cell is like an underground network in which the chemical structures of the metabolites go from one station to another by means of biochemical transformations. Up until now, it has been possible to determine the number of metabolites in a cell, tissue or organism, but studying their fluxes is technically much more complex and time consuming. Now, however, a group of researchers from the URV, CIBERDEM and IRB Barcelona have developed a new tool that makes this possible. Via nuclear magnetic resonance (NMR) techniques, it can take researchers hours to measure every sample, and the data are difficult to interpret. The new approach takes only 10 minutes per sample and obtains many more metabolites. Additionally, the results are much easier to interpret, as, metabolic traffic can be determined much more easily and effectively. It is a methodology based on NMR that measures hydrogen atoms (protons) in order to indirectly determine the number of carbon atoms that are marked in the chemical structures of the metabolites. The experiment is as follows: A nutrient that cells consume is marked with a stable isotope. Stable isotopes such as carbon 13 are not radioactive and do not represent any danger to organisms or the people who handle the samples. The proton is measured by NMR much more quickly and sensitively than the carbon, making it is possible to study the fluxes and the transformation dynamics of these nutrients inside the cell. So far, the efficacy of this new technique has been validated using human cancer cells, but it is directly applicable to any biological model. Understanding the reasons for some illnesses Diabetes, for example, is a metabolic syndrome in which the process begins long before the levels of glucose in the blood increase, because the body uses a variety of mechanisms to ensure that the concentration of this nutrient remains stable. And high levels of glucose are only seen in the blood when the disease is at an advanced stage. The new study describes a technique of studying the mechanisms that cause some tissues in the organism (for example, liver or pancreatic cells) to be unable to regulate levels of glucose or to become insensitive to it. The study of metabolic fluxes helps researchers to understand the reasons why the disease develops and the mechanism by which it does so. Therefore, it also helps in the process of diagnosis. In short, the new methodology offers great potential for practising physicians and molecular biologists to acquire greater understanding of certain diseases. The new technique, unlike more traditional techniques, does not use radioactivity to study the metabolism. The article, which has been published in the scientific journal Angewandte Chemie, shows the results of this work on cancer cells, but the researchers are sure that glucose, amino acids and fats marked with stable isotopes can be studied in other cells and even animals. The fact that they are not radioactive makes them much easier to work with because there is no need for special laboratory conditions. Explore further: New fat cell metabolism research could lead to new ways to treat diabetes and obesity More information: Maria Vinaixa et al, Positional Enrichment by Proton Analysis (PEPA): A One-DimensionalH-NMR Approach forC Stable Isotope Tracer Studies in Metabolomics, Angewandte Chemie International Edition (2017). DOI: 10.1002/anie.201611347


Canivell S.,CIBERDEM | Esmatjes E.,CIBERDEM
Surgery for Obesity and Related Diseases | Year: 2014

Background: There is scarce information about predictive factors of hypertension (HI) remission after bariatric surgery (BS). The aims of this study were to determine the clinical characteristics differentiating obese patients with and without HI and to evaluate the predictive factors associated with the risk of persistence of HI after BS.Patients and Methods: From January 2007 to December 2009, a review of patients who had undergone BS was performed. Patients were classified as hypertensive if having permanent use of antilll drugs or clinical BP ≥140/90 mm Hg. Weight, waist circumference (WC), and blood pressure were determined with standardized procedures.Results: Five hundred twenty-6 patients met the inclusion criteria; 264 (50%) were hypertensive, 74 (34%) of whom had type 2 diabetes. Before BS, older age, male gender, and greater WC differentiated hypertensive from normotensive patients. The prevalence of HI significantly fell to 35% (P < .0001) at 12 months after BS. The use of multivariate logistic regression showed that age >40, male gender and WC ≥ 130 cm were significant predictors of having HI before surgery. Regarding persistence of HI at the 12-month follow-up, the only independent predictors observed were time since diagnosis of HI > 10 years and the number of antilll drugs used. Presurgical BMI, WC, excess weight (EW), EW loss, surgical procedure, type 2 diabetes, and vitamin D status were not significant predictors.Conclusions: Bariatric surgery is associated with a high rate of HI remission. Older age, male gender, and higher WC differentiated hypertensive-obese from normotensive patients. After BS, longer duration and severity of HI were independently associated with no remission of HI. (Surg Obes Relat Dis 2014;10:661 665.). © 2014 American Society for Bariatric Surgery.

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