Milagro-Yoldi, F.I. (Fermín Ignacio)
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- Interaction between an adcy3 genetic variant and two weight-lowering diets affecting body fatness and body composition outcomes depending on macronutrient distribution: a randomized trial(MDPI AG, 2018) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Ortiz, L. (Lourdes); Corrales, F.J. (Fernando José); Goñi-Mateos, L. (Leticia); Milagro-Yoldi, F.I. (Fermín Ignacio); Cuervo, M. (Marta)The adenylate cyclase 3 (ADCY3) gene is involved in the regulation of several metabolic processes including the development and function of adipose tissue. The effects of the ADCY3 rs10182181 genetic variant on changes in body composition depending on the macronutrient distribution intake after 16 weeks of the dietary intervention were tested. The ADCY3 genetic variant was genotyped in 147 overweight or obese subjects, who were randomly assigned to one of the two diets varying in macronutrient content: a moderately-high-protein diet and a low-fat diet. Anthropometric and body composition measurements (DEXA scan) were recorded. Significant interactions between the ADCY3 genotype and dietary intervention on changes in weight, waist circumference, and body composition were found after adjustment for covariates. Thus, in the moderately-high-protein diet group, the G allele was associated with a lower decrease of fat mass, trunk and android fat, and a greater decrease in lean mass. Conversely, in the low-fat diet group carrying the G allele was associated with a greater decrease in trunk, android, gynoid, and visceral fat. Subjects carrying the G allele of the rs10182181 polymorphism may benefit more in terms of weight loss and improvement of body composition measurements when undertaking a hypocaloric low-fat diet as compared to a moderately-high-protein diet.
- Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake(Wiley Open Access, 2018) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Milagro-Yoldi, F.I. (Fermín Ignacio); Ramos-López, O. (Omar)Introduction: Dopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hy-pothesized associations of DNA methylation signatures at genes modulating DA sign -aling with obesity features, metabolic profiles, and dietary intake.Methods: An adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened.Results: After applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p <0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (C ACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the pres -ence or absence of abdominal obesity. Pathway analyses revealed a statistically sig-nificant contribution of the aforementioned genes to dopaminergic synapse transmission (p =4.78E−08). Furthermore,SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p <0.001) and carbohydrate (p <0.001) intakes.Conclusions: The results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition.
- Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells(Springer, 2017-02-08) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Martinez-Gonzalez, M.A. (Miguel Ángel); Fito, M. (Montserrat); Milagro-Yoldi, F.I. (Fermín Ignacio); Arpon, A. (Ana); Razquin, C. (Cristina); Ros, E. (Emilio); Casas, R. (Rosa); Estruch, R. (Ramón); Corella, D. (Dolores); Salas-Salvado, J. (Jordi)Epigenetic processes, including DNA methylation, might be modulated by environmental factors such as the diet, which in turn have been associated with the onset of several diseases such as obesity or cardiovascular events. Meanwhile, Mediterranean diet (MedDiet) has demonstrated favourable effects on cardiovascular risk, blood pressure, inflammation and other complications related to excessive adiposity. Some of these effects could be mediated by epigenetic modifications. Therefore, the objective of this study was to investigate whether the adherence to MedDiet is associated with changes in the methylation status from peripheral blood cells. A subset of 36 individuals was selected within the Prevención con Dieta Mediterránea (PREDIMED)-Navarra study, a randomised, controlled, parallel trial with three groups of intervention in high cardiovascular risk volunteers, two with a MedDiet and one low-fat control group. Changes in methylation between baseline and 5 years were studied. DNA methylation arrays were analysed by several robust statistical tests and functional classifications. Eight genes related to inflammation and immunocompetence (EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2, PPARGC1B) were finally selected as changes in their methylation levels correlated with adherence to MedDiet and because they presented sensitivity related to a high variability in methylation changes. Additionally, EEF2 methylation levels positively correlated with concentrations of TNF-α and CRP. This report is apparently the first showing that adherence to MedDiet is associated with the methylation of the reported genes related to inflammation with a potential regulatory impact.
- Effect of low-and non-calorie sweeteners on the gut microbiota: A review of clinical trials and cross-sectional studies(Elsevier, 2023) Milagro-Yoldi, F.I. (Fermín Ignacio); Navas-Carretero, S. (Santiago); Gauthier, P. (Pierre)Use of non-nutritive sweeteners (NNSs) has increased worldwide in recent decades. However, evidence from preclinical studies shows that sweetener consumption may induce glucose intolerance through changes in the gut microbiota, which raises public health concerns. As studies conducted on humans are lacking, the aim of this review was to gather and summarize the current evidence on the effects of NNSs on human gut microbiota. Only clinical trials and cross-sectional studies were included in the review. Regarding NNSs (i.e, saccharin, sucralose, aspartame, and stevia), only two of five clinical trials showed significant changes in gut microbiota composition after the intervention protocol. These studies concluded that saccharin and sucralose impair glycemic tolerance. In three of the four cross-sectional studies an association between NNSs and the microbial composition was observed. All three clinical trials on polyols (i.e, xylitol) showed prebiotic effects on gut microbiota, but these studies had multiple limitations (publication date, dosage, duration) that jeopardize their validity. The microbial response to NNSs consumption could be strongly mediated by the gut microbial composition at baseline. Further studies in which the potential personalized microbial response to NNSs consumption is acknowledged, and that include longer intervention protocols, larger cohorts, and more realistic sweetener dosage are needed to broaden these findings.
- High-throughput sequencing of microRNAs in peripheral blood mononuclear cells: identification of potential weight loss biomarkers(Public Library of Science, 2013) Martinez, J.A. (José Alfredo); Miranda, J. (Jonatan); Milagro-Yoldi, F.I. (Fermín Ignacio); Portillo, M.P. (María P.); Campión-Zabalza, J. (Javier); Fernandez-Quintela, A. (Alfredo)INTRODUCTION: MicroRNAs (miRNAs) are being increasingly studied in relation to energy metabolism and body composition homeostasis. Indeed, the quantitative analysis of miRNAs expression in different adiposity conditions may contribute to understand the intimate mechanisms participating in body weight control and to find new biomarkers with diagnostic or prognostic value in obesity management. OBJECTIVE: The aim of this study was the search for miRNAs in blood cells whose expression could be used as prognostic biomarkers of weight loss. METHODS: Ten Caucasian obese women were selected among the participants in a weight-loss trial that consisted in following an energy-restricted treatment. Weight loss was considered unsuccessful when <5% of initial body weight (non-responders) and successful when >5% (responders). At baseline, total miRNA isolated from peripheral blood mononuclear cells (PBMC) was sequenced with SOLiD v4. The miRNA sequencing data were validated by RT-PCR. RESULTS: Differential baseline expression of several miRNAs was found between responders and non-responders. Two miRNAs were up-regulated in the non-responder group (mir-935 and mir-4772) and three others were down-regulated (mir-223, mir-224 and mir-376b). Both mir-935 and mir-4772 showed relevant associations with the magnitude of weight loss, although the expression of other transcripts (mir-874, mir-199b, mir-766, mir-589 and mir-148b) also correlated with weight loss. CONCLUSIONS: This research addresses the use of high-throughput sequencing technologies in the search for miRNA expression biomarkers in obesity, by determining the miRNA transcriptome of PBMC. Basal expression of different miRNAs, particularly mir-935 and mir-4772, could be prognostic biomarkers and may forecast the response to a hypocaloric diet.
- High-fat diet feeding alters metabolic response to fasting/non fasting conditions. Effect on caveolin expression and insulin signalling.(BioMed Central, 2011) Martinez, J.A. (José Alfredo); Miguel-Vázquez, C. (Carlos) de; Milagro-Yoldi, F.I. (Fermín Ignacio); Gomez-Ruiz, A. (A.); Campión-Zabalza, J. (Javier)BACKGROUND: The effect of food intake on caveolin expression in relation to insulin signalling was studied in skeletal muscle and adipocytes from retroperitoneal (RP) and subcutaneous (SC) adipose tissue, comparing fasted (F) to not fasted (NF) rats that had been fed a control or high-fat (HF) diet for 72 days. METHODS: Serum glucose was analysed enzymatically and insulin and leptin by ELISA. Caveolins and insulin signalling intermediaries (IR, IRS-1 and 2 and GLUT4) were determined by RT-PCR and western blotting. Caveolin and IR phosphorylation was measured by immunoprecipitation. Data were analysed with Mann-Whitney U test. RESULTS: High-fat fed animals showed metabolic alterations and developed obesity and insulin resistance. In skeletal muscle, food intake (NF) induced activation of IR and increased expression of IRS-2 in control animals with normal metabolic response. HF animals became overweight, hyperglycaemic, hyperinsulinemic, hyperleptinemic and showed insulin resistance. In skeletal muscle of these animals, food intake (NF) also induced IRS-2 expression together with IR, although this was not active. Caveolin 3 expression in this tissue was increased by food intake (NF) in animals fed either diet. In RP adipocytes of control animals, food intake (NF) decreased IR and IRS-2 expression but increased that of GLUT4. A similar but less intense response was found in SC adipocytes. Food intake (NF) did not change caveolin expression in RP adipocytes with either diet, but in SC adipocytes of HF animals a reduction was observed. Food intake (NF) decreased caveolin-1 phosphorylation in RP but increased it in SC adipocytes of control animals, whereas it increased caveolin-2 phosphorylation in both types of adipocytes independently of the diet. CONCLUSIONS: Animals fed a control-diet show a normal response to food intake (NF), with activation of the insulin signalling pathway but without appreciable changes in caveolin expression, except a small increase of caveolin-3 in muscle. Animals fed a high-fat diet develop metabolic changes that result in insulin signalling impairment. In these animals, caveolin expression in muscle and adipocytes seems to be regulated independently of insulin signalling.
- Associations between olfactory pathway gene methylation marks, obesity features and dietary intakes(Springer Science and Business Media LLC, 2019) Santos, J.L. (José Luis); Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Zulet, M.A. (María Ángeles); Milagro-Yoldi, F.I. (Fermín Ignacio); Ramos-López, O. (Omar)Background: Olfaction is an important sense influencing food preferences, appetite, and eating behaviors. This hypothesis-driven study aimed to assess associations between olfactory pathway gene methylation signatures, obesity features, and dietary intakes. Methods: A nutriepigenomic analysis was conducted in 474 adults from the Methyl Epigenome Network Association (MENA) project. Anthropometric measurements, clinical data, and serum metabolic profiles of the study population were obtained from structured databases of the MENA cohorts. Habitual dietary intake was assessed using a validated semiquantitative food frequency questionnaire. DNA methylation was measured in circulating white blood cells by microarray (Infinium Human Methylation 450 K BeadChips). FDR values (p < 0.0001) were used to select those CpGs that showed the best correlation with body mass index (BMI) and waist circumference (WC). Pathway analyses involving the characterization of genes involved in the olfactory transduction system were performed using KEGG and pathDIP reference databases. Results: Overall, 15 CpG sites at olfactory pathway genes were associated with BMI (p < 0.0001) and WC (p < 0.0001) after adjustments for potential confounding factors. Together, methylation levels at the15 CpG sites accounted for 22% and 20% of the variability in BMI and WC (r 2 = 0.219, p < 0.001, and r 2 = 0.204, p < 0.001, respectively). These genes encompassed olfactory receptors (OR4D2, OR51A7, OR2T34, and OR2Y1) and several downstream signaling molecules (SLC8A1, ANO2, PDE2A, CALML3, GNG7, CALML6, PRKG1, and CAMK2D), which significantly regulated odor detection and signal transduction processes within the complete olfactory cascade, as revealed by pathway enrichment analyses (p = 1.94 × 10–10). Moreover, OR4D2 and OR2Y1 gene methylation patterns strongly correlated with daily intakes of total energy (p < 0.0001), carbohydrates (p < 0.0001), protein (p < 0.0001), and fat (p < 0.0001). Conclusions: The results of this study suggest novel relationships between olfactory pathway gene methylation signatures, obesity indices, and dietary intakes.
- Effect of TNF-Alpha on caveolin-1 expression and insulin signaling during adipocyte differentiation and in mature adipocytes(Karger, 2015) Martinez, J.A. (José Alfredo); Algarabel, M. (Miriam); Miguel-Vázquez, C. (Carlos) de; Milagro-Yoldi, F.I. (Fermín Ignacio); Palacios-Ortega, S. (Sara); Varela-Guruceaga, M. (Maider)Background/Aims: Tumor necrosis factor-α (TNF-α)-mediated chronic low-grade inflammation of adipose tissue is associated with obesity and insulin resistance. Caveolin-1 (Cav-1) is the central component of adipocyte caveolae and has an essential role in the regulation of insulin signaling. The effects of TNF-α on Cav-1 expression and insulin signaling during adipocyte differentiation and in mature adipocytes were studied. Methods: 3T3-L1 cells were differentiated (21 days) in the presence TNF-α (10 ng/mL) and mature adipocytes were also treated with TNF-α for 48 hours. Cav-1 and insulin receptor (IR) gene methylation were determined as well as Cav-1, IR, PKB/AKT-2 and Glut-4 expression and activation by real time RT-PCR and western blot. Baseline and insulin-induced glucose uptake was measured by the 2-[C14]-deoxyglucose uptake assay. Results: TNF-α slowed down the differentiation program, hindering the expression of some insulin signaling intermediates without fully eliminating insulin-mediated glucose uptake. In mature adipocytes, TNF-α did not compromise lipidstorage capacity, but downregulated the expression of the insulin signaling intermediates, totally blocking insulin-mediated glucose uptake. Insulin sensitivity correlated with the level of activated phospho-Cav-1 in both situations, strongly suggesting the direct contribution of Cav-1 to the maintenance of this physiological response. Conclusion: Cav-1 activation by phosphorylation seems to be essential for the maintenance of an active and insulin-sensitive glucose uptake.
- 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.
- Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives(Elsevier, 2012) Martinez, J.A. (José Alfredo); Miguel-Vázquez, C. (Carlos) de; Milagro-Yoldi, F.I. (Fermín Ignacio); Mansego-Talavera, M.L. (María Luisa)Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding the importance of the inheritance of these epigenetic marks.