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Ortega F.J.,CIBER ISCIII | Ortega F.J.,Hospital Dr Josep Trueta of Girona | Moreno-Navarrete J.M.,CIBER ISCIII | Moreno-Navarrete J.M.,Hospital Dr Josep Trueta of Girona | And 15 more authors.
International Journal of Obesity | Year: 2014

Objective: The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p53) in subjects who varied widely in terms of obesity and insulin resistance. We also analyzed different in vivo and in vitro models to try to comprehend the associations found in humans. Methods: p53 was analyzed in human adipose and isolated adipocytes, in high fat-fed and GLP-1R KO mice, during in vitro adipogenesis, and in adipocytes after high glucose, rosiglitazone and inflammatory conditions. The effects of surgery-induced weight loss and ex vivo metformin were also evaluated. Results: Omental (OM) p53 gene expression (+27%, P=0.001) and protein (+11%, P=0.04) were increased in obese subjects and high fat diet-induced obese mice (+86%, P=0.018). Although the obesity-associated inflammatory milieu was associated with increased OM p53, this was negatively related to insulin resistance and glycated hemoglobin, and positively with biomarkers for insulin sensitivity. Multiple linear regression analyses revealed that glycated hemoglobin (P<0.0001) and body mass index (P=0.048) contributed independently to explain 13.7% (P<0.0001) of the OM p53 variance. Accordingly, the improvement of insulin sensitivity with surgery-induced weight loss (+51%, P=0.01) and metformin (+42%, P=0.02) led to increased adipose p53. While the glucose-intolerant GLP-1R KO mice showed decreased mesenteric p53 (-45.4%, P=0.017), high glucose led to decreased p53 in pre-adipocytes (-27%, P<0.0001). Inflammatory treatments led to increased p53 (+35%, P<0.0001), while Rs downregulated this expression (-40%, P=0.005) in mature adipocytes. Conclusion: Inflammation and insulin resistance exert dual effects on adipose p53, which seems to be the final result of these opposing forces. © 2014 Macmillan Publishers Limited All rights reserved.


Frank-Raue K.,Endocrine Practice and Molecular Laboratory | Rybicki L.A.,Cleveland Clinic | Erlic Z.,Albert Ludwigs University of Freiburg | Schweizer H.,Albert Ludwigs University of Freiburg | And 39 more authors.
Human Mutation | Year: 2011

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected. © 2010 Wiley-Liss, Inc.


Menendez J.A.,Catalan Institute of Nanoscience and Nanotechnology | Menendez J.A.,Girona Biomedical Research Institute IDIBGI | Menendez J.A.,Hospital Dr Josep Trueta Of Girona | Joven J.,Rovira i Virgili University
Advances in Experimental Medicine and Biology | Year: 2014

We are as old as our adult stem cells are; therefore, stem cell exhaustion is considered a hallmark of aging. Our tumors are as aggressive as the number of cancer stem cells (CSCs) they bear because CSCs can survive treatments with hormones, radiation, chemotherapy, and molecularly targeted drugs, thus increasing the difficulty of curing cancer. Not surprisingly, interest in stem cell research has never been greater among members of the public, politicians, and scientists. But how can we slow the rate at which our adult stem cells decline over our lifetime, reducing the regenerative potential of tissues, while efficiently eliminating the aberrant, life-threatening activity of "selfish", immortal, and migrating CSCs? Frustrated by the gene-centric limitations of conventional approaches to aging diseases, our group and other groups have begun to appreciate that bioenergetic metabolism, i.e., the production of fuel & building blocks for growth and division, and autophagy/mitophagy, i.e., the quality-control, self-cannibalistic system responsible for "cleaning house" and "recycling the trash", can govern the genetic and epigenetic networks that facilitate stem cell behaviors. Indeed, it is reasonable to suggest the existence of a "metabostem" infrastructure that operates as a shared hallmark of aging and cancer, thus making it physiologically plausible to maintain or even increase the functionality of adult stem cells while reducing the incidence of cancer and extending the lifespan. This "metabostemness" property could lead to the discovery of new drugs that reprogram cell metabotypes to increase the structural and functional integrity of adult stem cells and positively influence their lineage determination, while preventing the development and aberrant function of stem cells in cancer tissues. While it is obvious that the antifungal antibiotic rapamycin, the polyphenol resveratrol, and the biguanide metformin already belong to this new family of metabostemness-targeting drugs, we can expect a rapid identification of new drug candidates (e.g., polyphenolic xenohormetins) that reverse or postpone "geroncogenesis", i.e., aging-induced metabolic decline as a driver of tumorigenesis, at the stem cell level. © 2014 Springer International Publishing Switzerland.


Ortega F.J.,Hospital Dr Josep Trueta Of Girona | Ortega F.J.,CIBER ISCIII | Mercader J.M.,Barcelona Supercomputing Center | Moreno-Navarrete J.M.,Hospital Dr Josep Trueta Of Girona | And 24 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Molecular mechanisms associated with physiological variations in adipose tissue (AT) are not fully recognized. The most recent reports highlight the critical relevance of microRNAs (miRNAs) found in AT. Objective: To identify changes in messenger RNA (mRNA) and miRNA expressions and their interaction in human AT before and after surgery-induced weight loss. Research Design and Setting: Genome-wide mRNA and miRNA expressions were assessed by microarrays in abdominal subcutaneous AT of 16 morbidly obese women before and 2 years after laparoscopic Roux-en-Y gastric bypass. The association of changes in miRNAs with their respective mRNA targets was studied. The results were replicated in publicly available microarray datasets. Validation was made by real-time polymerase chain reaction in additional fat samples from 26 age-matched lean women and in isolated human adipocytes. Results: A total of 5018 different mRNA probe sets and 15 miRNAs were differentially expressed after surgery-induced weight loss. The clustering of similar expression patterns for gene products with related functions revealed molecular footprints that elucidate significant changes in cell cycle, development, lipid metabolism, and the inflammatory response. The participation of inflammation was demonstrated by results assessed in isolated adipocytes. Interestingly, when transcriptomes were analyzed taking into account the presence of miRNA target sites, miRNA targetmRNAs were upregulated in obeseAT(P value=2×10-181) and inflamed adipocytes (P value=4×10-61), according to the number of target sites harbored by each transcript. Conclusions: Current findings suggest impaired miRNA target gene expression in obese AT in close association with inflammation, both improving after weight loss. Copyright © 2015 by the Endocrine Society.


Lopez Navarro E.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Ortega F.J.,Hospital Dr Josep Trueta Of Girona | Ortega F.J.,CIBER ISCIII | Francisco-Busquets E.,Gynecological Clinic GIREXX | And 7 more authors.
Thyroid | Year: 2016

Background: Thyroid hormones are known to exert an important role in reproduction. The objective of this study was to evaluate the expression of thyroid hormone receptors (TR) in granulosa (GC) and cervical cells (CC) of infertile euthyroid women. Methods: In a cross-sectional study, 31 consecutive infertile and 18 fertile women undergoing oocyte retrieval procedures were investigated. The expression of TRα1, TRα2, and TRβ was evaluated in GCs and uterine CC from infertile and fertile euthyroid women. β2 adrenergic receptor (ADRβ2) mRNA levels and the expression of genes linked to fertility such as gremlin-1 (GREM1), hyaluronan synthase 2 (HAS2), and prostaglandin-endoperoxide synthase 2 (PTGS2) were also evaluated. Results: In GCs, the expression of the thyroid hormone receptor TRα2, which exerts a dominant negative effect, increased with age in all women tested. TRα2 mRNA was increased in infertile versus fertile women, in parallel to decreased ADRβ2 mRNA. As expected, the expression of genes associated with fertility (i.e., GREM1 and PTGS2) was downregulated in infertile women, in parallel to decreased ADRβ2 mRNA and increased TRα2 mRNA. In uterine CCs, a positive association of ADRβ2 mRNA with TRα1:TRα2 ratio was observed. Importantly, GCs from infertile women whose oocytes did not result in pregnancy had increased expression of TRα2 (p = 0.017) and lower ADRβ2 (p = 0.008), GREM1 (p = 0.003), and PTGS2 (p = 0.002) mRNAs than fertile women whose oocytes resulted in pregnancy. Infertile women also showed more TRα2 (p = 0.033) mRNA in CCs than fertile women whose oocytes resulted in pregnancy. Conclusions: The expression of different markers of intracellular thyroid function is linked to fertility status. © Mary Ann Liebert, Inc. 2016.


Esteve E.,Hospital Dr Josep Trueta of Girona | Esteve E.,CIBER ISCIII | Ricart W.,Hospital Dr Josep Trueta of Girona | Ricart W.,CIBER ISCIII | And 2 more authors.
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2011

Purpose of Review: The prevalence of obesity, insulin resistance and type 2 diabetes has steadily increased in the last decades. In addition to the genetic and environmental factors, gut microbiota may play an important role in the modulation of intermediary phenotypes leading to metabolic disease. Recent Findings: Obesity and type 2 diabetes are associated with specific changes in gut microbiota composition. The mechanisms underlying the association of specific gut microbiota and metabolic disease include increasing energy harvest from the diet, changes in host gene expression, energy expenditure and storage, and alterations in gut permeability leading to metabolic endotoxemia, inflammation and insulin resistance. In some studies, the modifications of gut microbiota induced by antibiotics, prebiotics and probiotics led to improved inflammatory activity in parallel to amelioration of insulin sensitivity and decreased adiposity. However, these effects were mainly observed in animal models. Their extrapolation to humans awaits further studies. Summary: The fascinating role of gut microbiota on metabolic disease opens new avenues in the treatment of obesity, insulin resistance and type 2 diabetes. A co-evolutionary clue for microbiota and insulin resistance is suggested. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Prats-Puig A.,Institute Dinvestigacio Biomedica Of Girona | Ortega F.J.,Hospital Dr Josep Trueta of Girona | Ortega F.J.,CIBER ISCIII | Mercader J.M.,Barcelona Supercomputing Center | And 10 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Circulating microRNAs (miRNAs) are valuable biomarkers of metabolic diseases and potential therapeutic targets in this field. Objective: Our objective was to define the circulating pattern of miRNAs in childhood obesity. Design, Settings, and Main Outcome Measure: The genome-wide circulating miRNA profile was assessed by RT-PCR in 10 boys (5 lean and 5 obese children). The most relevant miRNAs were cross-sectionally validated in 85 lean versus 40 obese children (63 boys and 62 girls) and longitudinally evaluated in samples from the same children when they were ∼7 and ∼10 years old (23 boys and 22 girls). Results: The cross-sectional validation study disclosed that 15 specific circulating miRNAs were significantly deregulated in prepubertal obesity, including the decreased miR-221 and miR-28-3p and increased concentrations in plasma of miR-486-5p, miR-486-3p, miR-142-3p, miR-130b, and miR-423-5p (all P <.0001). The circulating concentration of these miRNAs was significantly associated with body mass index and other measures of obesity such as percent fat mass, waist, regional fat distribution and with laboratory parameters such as homeostasis model assessment of insulin resistance, high-molecular-weight adiponectin, C-reactive protein, and circulating lipids in concordance with anthropometric associations. Plasma concentrations of 10 of these circulating miRNAs changed significantly and differently during the 3-year follow-up in children who increased or decreased their normalized weight. Conclusion: This study provides the first evidence that circulating miRNAs are deregulated in prepubertal obese children. Thus, the very early detection of an abnormal circulating miRNA profile may be a promising strategy to identify obese children who may suffer from metabolic abnormalities. Copyright © 2013 by The Endocrine Society.


Redon J.,University of Valencia | Pascual-Izuel J.M.,Hospital Of Sagunto | Rodilla E.,Hospital Of Sagunto | Vicente A.,University of Valencia | And 5 more authors.
Blood Pressure | Year: 2014

Introduction. The main objective was to compare the mean change in augmentation index of hypertensive patients treated with nebivolol or atenolol. Methods. Multicenter, double-blind randomized study conducted in six Spanish centers. We enrolled outpatients between the ages of 40 and 65 years with mild or moderate essential hypertension (systolic blood pressure, SBP ≥ 140 mmHg to ≤ 179 mmHg and diastolic blood pressure, DBP ≥ 90 mmHg to ≤ 109 mmHg after a 2-week run-in placebo period). Patients received nebivolol 5 mg or atenolol 50 mg once daily. At week 3, atenolol could be titrated up to 100 mg qd for non-responders. Additionally, patients not achieving normal blood pressure after 6 weeks could be treated with 25 mg hydrochlorothiazide. Follow-up visits were at 3, 6 and 10 weeks. Results. The final study population of 138 patients (58% men; median age 52.6 years, range 40-67 years) was randomized into two groups of 69 patients each. Baseline characteristics of the two groups were similar. At the screening visit, 69% presented with mild hypertension. Nebivolol modified the mean augmentation index to a lesser extent than atenolol after 10 weeks (mean difference 3.1%, 95% CI 0.55-5.69; p = 0.027). A higher proportion of patients in the atenolol group required a diuretic. Reductions in central aortic pressure and peripheral arterial pressure were similar for both treatment groups. Conclusions. The study confirms that nebivolol produces a less pronounced impact on augmentation index than atenolol. © 2014 Scandinavian Foundation for Cardiovascular Research.


PubMed | Barcelona Supercomputing Center, Institute Dinvestigacio Biomedica Of Girona Idibgi and Hospital Dr Josep Trueta of Girona
Type: | Journal: International journal of obesity (2005) | Year: 2017

Many controversies regarding the association of liver miRNAs with obesity and nonalcoholic fatty liver diseases (NAFLD) call for additional validations. This study sought to investigate variations in genes and hepatic miRNAs in a sample of obese patients with or without NAFLD and human hepatocytes.Sixty non-consecutive obese women following bariatric surgery were recruited. Subjects were classified as NAFLD (n=17), borderline (n=24), and controls (n=19) with normal enzymatic profile, liver histology, and ultrasound assessments. Profiling of 744 miRNAs was performed in 8 obese women with no sign of hepatic disease and 11 NAFLD patients. Additional validation and expression of genes related to de novo fatty acid (FA) biosynthesis, uptake, transport and -oxidation; glucose metabolism, and inflammation was tested in the extended sample. Induction of NAFLD-related genes and miRNAs was examined in HepG2 cells and primary human hepatocytes treated with palmitic acid (PA), a combination of palmitate and oleic acid, or high-glucose and insulin (HG) mimicking insulin resistance in NAFLD.In the discovery sample, 14 miRNAs were associated with NAFLD. Analyses in the extended sample confirmed decreased miR-139-5p, miR-30b-5p, miR-122-5p, and miR-422a, and increased miR-146b-5p in obese subjects with NAFLD. Multiple linear regression analyses disclosed that NAFLD contributed independently to explain miR-139-5p (P=0.005), miR-30b-5p (P=0.005), miR-122-5p (P=0.021), miR-422a (P=0.007), and miR-146a (P=0.033) expression variance after controlling for confounders. Decreased miR-122-5p in liver was associated with impaired FA usage. Expression of inflammatory and macrophage-related genes was opposite to decreased miR-30b-5p, miR-139-5p, and miR-422a, while increased miR-146b-5p was associated with FABP4 and decreased glucose metabolism and FA mobilization. In partial agreement, PA (but not HG) led to decreased miR-139-5p, miR-30b-5p, miR-422a, and miR-146a in vitro, in parallel with increased lipogenesis and FA transport, decreased glucose metabolism, and diminished FA oxidation.This study confirms decreased liver glucose and lipid metabolism but increased FA biosynthesis coupled with changes in five unique miRNAs in obese patients with NAFLD.International Journal of Obesity accepted article preview online, 25 January 2017. doi:10.1038/ijo.2017.21.

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