Cordero, P. (Paul)
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- Obesity and ischemic stroke modulate the methylation levels of KCNQ1 in white blood cells(Oxford University Press, 2015) Martinez, J.A. (José Alfredo); Gomez-Uriz, A.M. (Ana María); Blazquez, V. (Vanessa); De-Arce, A. (Ana); Milagro-Yoldi, F.I. (Fermín Ignacio); Goyenechea, E. (Estíbaliz); Cordero, P. (Paul); Mansego-Talavera, M.L. (María Luisa); Martinez-Zabaleta, M. (Maite); Abete, I. (Itziar); Campión-Zabalza, J. (Javier); Lopez-de-Munain, A. (Adolfo)ABSTRACT Obesity and stroke are multifactorial diseases in which genetic, epigenetic and lifestyle factors are involved. The research aims were, first, the description of genes with differential epigenetic regulation obtained by an “omics” approach in patients with ischemic stroke and, second, to determine the importance of some regions of these selected genes in biological processes depending on the BMI. A case-control study using two populations was designed. The first population consisted of 24 volunteers according to stroke/non-stroke and normal weight/obesity conditions. The second population included 60 stroke patients and 55 controls classified by adiposity. DNA from the first population was analyzed with a methylation microarray, showing 80 CpG sites differentially methylated in stroke and 96 CpGs in obesity, whereas 59 CpGs showed interaction. After validating these data by MassArray Epityper, the promoter region of PM20D1 gene was significantly hypermethylated in stroke patients. One CpG site at CALD1 gene showed an interaction between stroke and obesity. Two CpGs located in the genes WT1 and KCNQ1 were significantly hypermethylated in obese patients. In the second population, KCNQ1 was also hypermethylated in the obese subjects. Two CpGs of this gene were subsequently validated by methylation-sensitive high-resolution melting. Moreover, KCNQ1 methylation levels were associated with plasma KCNQ1 protein concentrations. In conclusion, obesity induced changes in the KCNQ1 methylation pattern which were also dependent on stroke. Furthermore, the epigenetic marks differentially methylated in the stroke patients were dependent on the previous obese state. These DNA methylation patterns could be used as future potential stroke biomarkers.
- Transcriptomic modifications and epigenetic control induced by a hypercaloric diet and the supplementation with methyl donors: perinatal effects and during adult life(Servicio de Publicaciones de la Universidad de Navarra, 2013) Cordero, P. (Paul); Martinez, J.A. (José Alfredo); Milagro-Yoldi, F.I. (Fermín Ignacio); Campión-Zabalza, J. (Javier)Non-Alcoholic Fatty Liver Disease (NAFLD) is the main hepatic manifestations of metabolic syndrome. Some animal models of NAFLD are associated with dietary depletion of methyl donor substrates. The aim of this research was to study in adult rats the effect of dietary supplementation with promethylating substrates (betaine, choline, folic acid and vitamin B12) during different periods of life, on liver fat accumulation induced by a high-fat-sucrose (HFS) obesogenic dietary intake during adulthood, as well as the nutrigenomic and epigenomic mechanisms implicated in these processes. Animal models of obesity were achieved by HFS feeding, which were supplemented with a methyl donor cocktail to analyse the effect on adult male and female rats and the response to an obesogenic diet during adult life depending on perinatal maternal nutrition. In order to deepen into the mechanisms implicated we carried out magnetic resonance and plasma biochemical analysis, as well as transcriptomic (microarray and RT-qPCR) and DNA methylation-based techniques (mass spectrometry and radioactivity-related), among others. Obesogenic dietary intake was associated with an obese phenotype, while methyl donor supplementation decreased diet-induced liver fat accumulation. High-fat-sucrose diet intake and methyl donor supplementation showed changes on some plasma biochemical profile and on liver mRNA levels of genes related to obesity, lipid metabolism, liver injury or DNA methylation. Epigenetic features, as DNA methylation profile (both global and specific) were also characterized. Dietary supplementation with a promethylating cocktail prevented against high-fat-sucrose diet induced liver fat accumulation in rats. This protective effect is sex-independent and occurs by supplementing during adult life or after maternal intake during lactation. Hepatic transcriptome and epigenome are changed by obesogenic diet intake and by methyl donor dietary supplementation, affecting obesity (LepR), lipid metabolism (AcacA, Fasn, Srebf1, Srebf2, Agpat3), liver damage (Btc, Mme, Fat1) or DNA methylation (Dnmts) related genes.
- Epigenética nutricional: una pieza clave en el rompecabezas de la obesidad(Sociedad Española para el Estudio de la Obesidad, 2010) Martinez, J.A. (José Alfredo); Milagro-Yoldi, F.I. (Fermín Ignacio); Cordero, P. (Paul); Campión-Zabalza, J. (Javier)La obesidad es el resultado de la interacción de la genética con factores dietéticos y estilos de vida. La nutrigenómica estudia la influencia de la nutrición y los nutrientes en la expresión génica. Actualmente, como punto de vista complementario, surge la epigenética, centrada en los mecanismos que regulan la expresión del ADN sin alterar su secuencia de nucleótidos.
- Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet(Springer, 2013) Martinez, J.A. (José Alfredo); Gomez-Uriz, A.M. (Ana María); Milagro-Yoldi, F.I. (Fermín Ignacio); Cordero, P. (Paul); Campión-Zabalza, J. (Javier)Non-alcoholic fatty liver disease (NAFLD) is one of the first hepatic manifestations of metabolic syndrome, whose progression can lead to cirrhosis and hepatic carcinoma. Interestingly, methyl donor supplementation could improve obesogenic diet-induced hepatic triglyceride accumulation. The aim of this research is to describe methyl donor effects on a high-fat-sucrose (HFS) diet in both sexes and epigenetic changes induced on fatty acid synthase (FASN) promoter methylation pattern as well as gene expression of NAFLD key metabolic genes. Twenty-four male and 28 female Wistar rats were assigned to three dietary groups: control, HFS, and HFS supplemented with methyl donors (choline, betaine, vitamin B12, and folic acid). After 8 weeks of treatment, somatic, biochemical, mRNA, and epigenetic measurements were performed. Rats fed the HFS diet presented an overweight phenotype and alterations in plasma biochemical measurements. Methyl donor supplementation reverted the HFS-diet-induced hepatic triglyceride accumulation. Analysis of FASN promoter cytosine methylation showed changes in both sexes due to the obesogenic diet at -1,096, -780, -778, and -774 CpG sites with respect to the transcriptional start site. Methyl donor supplementation modified DNA methylation at -852, -833, -829, -743, and -733 CpGs depending on the sex. RT-PCR analysis confirmed that FASN expression tended to be altered in males. Our findings reinforce the hypothesis that methyl donor supplementation can prevent hepatic triglyceride accumulation induced by obesogenic diets in both sexes. Changes in liver gene expression profile and epigenetic-mediated mechanisms related to FASN DNA hypermethylation could be involved in methyl donor-induced NAFLD improvement.
- Fat-to-glucose interconversion by hydrodynamic transfer of two glyoxylate cycle enzyme genes(BioMed Central, 2008) Martinez, J.A. (José Alfredo); Marzo, F. (F.); Milagro-Yoldi, F.I. (Fermín Ignacio); Cordero, P. (Paul); Campión-Zabalza, J. (Javier)The glyoxylate cycle, which is well characterized in higher plants and some microorganisms but not in vertebrates, is able to bypass the citric acid cycle to achieve fat-to-carbohydrate interconversion. In this context, the hydrodynamic transfer of two glyoxylate cycle enzymes, such as isocytrate lyase (ICL) and malate synthase (MS), could accomplish the shift of using fat for the synthesis of glucose. Therefore, 20 mice weighing 23.37 +/- 0.96 g were hydrodinamically gene transferred by administering into the tail vein a bolus with ICL and MS. After 36 hours, body weight, plasma glucose, respiratory quotient and energy expenditure were measured. The respiratory quotient was increased by gene transfer, which suggests that a higher carbohydrate/lipid ratio is oxidized in such animals. This application could help, if adequate protocols are designed, to induce fat utilization for glucose synthesis, which might be eventually useful to reduce body fat depots in situations of obesity and diabetes
- Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet(Springer, 2011) Martinez, J.A. (José Alfredo); Steemburgo, T. (Thais); Javierre, B.M. (B. M.); Milagro-Yoldi, F.I. (Fermín Ignacio); Goyenechea, E. (Estíbaliz); Cordero, P. (Paul); Campión-Zabalza, J. (Javier)Obesity-associated adipose tissue enlargement is characterized by an enhanced proinflammatory status and an elevated secretion of adipokines such as leptin and cytokines such as TNF-alpha. Among the different mechanisms that could underlie the interindividual differences in obesity, epigenetic regulation of gene expression has emerged as a potentially important determinant. Therefore, twenty-seven obese women (age: 32-50 years; baseline Body Mass Index, BMI: 34.4±4.2 Kg/m2) were prescribed an eight-week Low-Calorie-Diet and epigenetic marks were assessed. Baseline and endpoint anthropometric parameters were measured and blood samples were drawn. Genomic DNA and RNA from adipose tissue biopsies were isolated before and after the dietary intervention. Leptin and TNF-alpha promoter methylation were measured by MSP after bisulfite treatment and gene expression was also analyzed. Obese women with a successful weight loss (≥5% of initial body weight, n=21) improved the lipid profile and fat mass percentage (-12%, p<0.05). Both systolic (-5%, p<0.05) and diastolic (-8%, p<0.01) blood pressures significantly decreased. At baseline women with better response to the dietary intervention showed lower promoter methylation levels of leptin (-47%, p<0.05) and TNF-alpha (-39%, p=0.071) than the non-responder group (n=6), while no differences were found between responder and non-responder group in leptin and TNF-alpha gene expression analysis. These data suggest that leptin and TNF-alpha methylation levels could be used as epigenetic biomarkers concerning the response to a Low-Calorie-Diet. Indeed, methylation profile could help to predict the susceptibility to weight loss as well as some comorbidities such as hypertension or type 2 diabetes.
- Maternal methyl donors supplementation during lactation prevents the hyperhomocysteinemia induced by a high-fat-sucrose intake by dams(MDPI, 2013) Martinez, J.A. (José Alfredo); Milagro-Yoldi, F.I. (Fermín Ignacio); Cordero, P. (Paul); Campión-Zabalza, J. (Javier)Maternal perinatal nutrition may program offspring metabolic features. Epigenetic regulation is one of the candidate mechanisms that may be affected by maternal dietary methyl donors intake as potential controllers of plasma homocysteine levels. Thirty-two Wistar pregnant rats were randomly assigned into four dietary groups during lactation: control, control supplemented with methyl donors, high-fat-sucrose and high-fat-sucrose supplemented with methyl donors. Physiological outcomes in the offspring were measured, including hepatic mRNA expression and global DNA methylation after weaning. The newborns whose mothers were fed the obesogenic diet were heavier longer and with a higher adiposity and intrahepatic fat content. Interestingly, increased levels of plasma homocysteine induced by the maternal high-fat-sucrose dietary intake were prevented in both sexes by maternal methyl donors supplementation. Total hepatic DNA methylation decreased in females due to maternal methyl donors administration, while Dnmt3a hepatic mRNA levels decreased accompanying the high-fat-sucrose consumption. Furthermore, a negative association between Dnmt3a liver mRNA levels and plasma homocysteine concentrations was found. Maternal high-fat-sucrose diet during lactation could program offspring obesity features, while methyl donors supplementation prevented the onset of high hyperhomocysteinemia. Maternal dietary intake also affected hepatic DNA methylation metabolism, which could be linked with the regulation of the methionine-homocysteine cycle.
- A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss(Federation of American Society of Experimental Biology, 2011) Martinez, J.A. (José Alfredo); Gomez-Uriz, A.M. (Ana María); Zulet, M.A. (María Ángeles); Milagro-Yoldi, F.I. (Fermín Ignacio); Goyenechea, E. (Estíbaliz); Cordero, P. (Paul); Abete, I. (Itziar); Campión-Zabalza, J. (Javier)Epigenetics could help to explain individual differences in weight loss after an energy-restriction intervention. Here, we identify novel potential epigenetic biomarkers of weight loss, comparing DNA methylation patterns of high and low responders to a hypocaloric diet. Twenty-five overweight or obese men participated in an 8-wk caloric restriction intervention. DNA was isolated from peripheral blood mononuclear cells and treated with bisulfite. The basal and endpoint epigenetic differences between high and low responders were analyzed by methylation microarray, which was also useful in comparing epigenetic changes due to the nutrition intervention. Subsequently, MALDI-TOF mass spectrometry was used to validate several relevant CpGs and the surrounding regions. DNA methylation levels in several CpGs located in the ATP10A and CD44 genes showed statistical baseline differences depending on the weight-loss outcome. At the treatment endpoint, DNA methylation levels of several CpGs on the WT1 promoter were statistically more methylated in the high than in the low responders. Finally, different CpG sites from WT1 and ATP10A were significantly modified as a result of the intervention. In summary, hypocaloric-diet-induced weight loss in humans could alter DNA methylation status of specific genes. Moreover, baseline DNA methylation patterns may be used as epigenetic markers that could help to predict weight loss.
- Impact of hypoxia exposure, combined with induced maternal obesity, on gestating sprague dawley dams(Elmer Press, 2016) Martinez, J.A. (José Alfredo); Marinoni, M. (M.); Gonzalez-Muniesa, P. (Pedro); Cordero, P. (Paul); Campión-Zabalza, J. (Javier)Abstract Obesity is now considered to be a global epidemic, impacting a great number of women and leading to a higher risk of obstetrical and gestational complications. One of such possible adverse outcomes in gestating female is placental hypoxia, which has been related to vascular remodeling and hypertension, as well as adaptive phenomena to reduce levels of oxidative stress and damage. A pool of female Sprague Dawley rats (n=63) was first assigned into two dietary groups (Control and High Sugar). Following mating, the pregnant rats (n=39) were again distributed into two oxygen treatment groups (Normoxia and Hypoxia) for 3 weeks, and tissue sampling and biochemical analyses were carried out. The main results of this study are the following: 1) Hypoxia during gestation may lead to a reduction in the average number of pups per mother, 2) Hypoxia during gestation treatment may lead to a decrease in maternal serum TG levels, and consequentially 3) Hypoxia during gestation may lead to a reduction in TyG Index levels. These results suggest that hypoxia could generate a beneficial response in pregnant Sprague Dawley rats to salvage both maternal and fetal viability. Thus, reproducing mild hypoxic conditions could result being a viable therapeutic option in preventing gestational adversities. In conclusion, progress was made in recognizing the possible role of a mild hypoxic environment in stimulating a maternal protective response.
- Molecular basis of the inflammation related to obesity(Hindawi Limited, 2019) Garcia-Diaz, D.F. (Diego F.); Gonzalez-Muniesa, P. (Pedro); Crujeiras, A.B. (Ana B.); Stachowska, E. (Ewa); Cordero, P. (Paul)Almost two thousand millions of adults suffer from overweight or obesity in the world [1]. After decades of research, we understand that the solution to this problem is not easy, as the pernicious trend is still increasing. This disease is defined as an excessive fat accumulation together with a moderate but chronic inflammation. This accompanying proinflammatory status is considered the link between obesity and the development of its related comorbidities such as insulin resistance and type 2 diabetes, cardiovascular diseases, cancer, and nonalcoholic fatty liver disease .