Institute Dinvestigacio Biomedica Of Girona Idibgi

Girona, Spain

Institute Dinvestigacio Biomedica Of Girona Idibgi

Girona, Spain
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Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Ortega F.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Serrano M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Rodriguez-Hermosa J.I.,Institute Dinvestigacio Biomedica Of Girona Idibgi | And 3 more authors.
International Journal of Obesity | Year: 2014

Objective: FSP27 KO mice showed enhanced expression of mitochondrial genes, increased mitochondrial activity and smaller lipid droplets. Here, we aimed to investigate lipid droplet protein (CIDEC/FSP27 and perilipinA (PLIN1)) gene expression in human adipose tissue in association with obesity, insulin resistance and mitochondrial gene expression. Design and subjects: In cohort 1, CIDEC/FSP27, PLIN1, adipogenic (FASN, ACACA, PPARG, GLUT4) and mitochondrial (PPARGC1A, PPARGC1B, TFAM, MT-CO3) gene expression were analyzed in 171 adipose tissue samples (88 visceral adipose tissue (VAT) and 83 subcutaneous adipose tissue (SAT) depots) and in a time course experiment in human subcutaneous and visceral preadipocytes using real-time PCR. In cohort 2, the effects of bariatric surgery-induced weight loss were also evaluated in six caucasian morbidly obese women. Additionally, in cohort 2 FSP27 and PLIN1 protein levels were measured using western blotting. Results: CIDEC/FSP27 (1.03±0.52 vs 0.49±0.23 relative gene expression unit (R.U.), P<0.0001) and PLIN1 (1.32±0.82 vs 0.63±0.42 R.U., P<0.0001) gene were significantly more expressed in SAT than in VAT. In VAT, CIDEC/FSP27 and PLIN1 gene expression decreased with body mass index, percent fat mass, fasting glucose, fasting insulin, HOMA and were positively associated with adipogenic (PPARG, GLUT4, FASN and ACACA) and mitochondrial biogenesis (PPARGC1A, PPARGC1B, TFAM and MT-CO3)-related genes. Mitochondrial gene expression increased during adipocyte differentiation in parallel to FSP27 and PLIN1 and other adipogenic genes. After bariatric surgery-induced weight loss, PLIN1 and CIDEC/FSP27 gene and protein expression in SAT increased significantly in parallel to adipogenic and mitochondrial genes. Conclusion: These findings suggest a positive functional interaction between CIDEC/FSP27, PLIN1 and mitochondrial biogenesis-related genes in human adipose tissue. © 2014 Macmillan Publishers Limited All rights reserved.


Ortega F.J.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Ortega F.J.,CIBER ISCIII | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Fernandez-Real J.M.,CIBER ISCIII
Hormone and Metabolic Research | Year: 2013

Recent findings in adipose tissue (AT) have uncovered negative interactions among obesity, lipogenesis, and fatty acid (FA) storage, perhaps in response to the increased production of proinflammatory cytokines and transcription factors. Emerging evidence highlights that local hypoxia, generation of reactive oxygen and nitrogen species, increased immune cells infiltration and activation, senescence, inflammation, energy consumption, and decreased lipogenesis in the AT are interrelated and may lead to impaired cytokine and hormonal secretion by adipocytes, and ectopic fat deposition in obesity that strengths the increased risk of suffering metabolic disorders in obese subjects. The information summarized in this review attempts to defend the interdependent relationship of these proofs of concept, supporting the idea that inflamed and dysfunctional AT are synonymous when referring to obesity. This may happen in severe obese subjects with a large and long-lasting fat excess, when fat depots have reached the point in which excessive fat storage, cell density, and diminished oxygen availability promote decreased lipo/adipogenesis and increased lipolysis and FA release. This response may be induced by an important inflammatory component that promotes angiogenesis and insulin resistance, but also by leptin and the increase of T3 in hyperplastic AT. © 2013 Georg Thieme Verlag KG Stuttgart New York.


Manco M.,Bambino Gesu Childrens Hospital and Research Institute | Fernandez-Real J.M.,University of Franca | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Fernandez-Real J.M.,CIBER ISCIII
BMC Medicine | Year: 2012

In patients with metabolic syndrome, body iron overload exacerbates insulin resistance, impairment of glucose metabolism, endothelium dysfunction and coronary artery responses. Conversely, iron depletion is effective to ameliorate glucose metabolism and dysfunctional endothelium. Most of its effectiveness seems to occur through the amelioration of systemic and hepatic insulin resistance.In a study published by BMC Medicine, Michalsen et al. demonstrated a dramatic improvement of blood pressure, serum glucose and lipids after removing 550 to 800 ml of blood in subjects with metabolic syndrome. This effect was apparently independent of changes in insulin resistance, in contrast to previous cross-sectional and cohort studies investigating the association between iron overload, insulin resistance and cardiovascular disease.Despite drawbacks in the study design, its findings may lead the way to investigations aimed at exploring iron-dependent regulatory mechanisms of vascular tone in healthy individuals and patients with metabolic disease, thus providing a rationale for novel preventive and therapeutic strategies to counteract hypertension.Please see related article: http://www.biomedcentral.com/1741-7015/10/54. © 2012 Manco and Fernandez-Real; licensee BioMed Central Ltd.


Ortega F.J.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Pardo G.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Sabater M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | And 7 more authors.
PLoS ONE | Year: 2010

Background: Potential regulators of adipogenesis include microRNAs (miRNAs), small non-coding RNAs that have been recently shown related to adiposity and differentially expressed in fat depots. However, to date no study is available, to our knowledge, regarding miRNAs expression profile during human adipogenesis. Thereby, the aim of this study was to investigate whether miRNA pattern in human fat cells and subcutaneous adipose tissue is associated to obesity and comorbidities and whether miRNA expression profile in adipocytes is linked to adipogenesis. Methodology/Principal Findings:We performed a global miRNA expression microarray of 723 human and 76 viral mature miRNAs in human adipocytes during differentiation and in subcutaneous fat samples from non-obese (n = 6) and obese with (n = 9) and without (n = 13) Type-2 Diabetes Mellitus (DM-2) women. Changes in adipogenesis-related miRNAs were then validated by RT-PCR. Fifty of 799 miRNAs (6.2%) significantly differed between fat cells from lean and obese subjects. Seventy miRNAs (8.8%) were highly and significantly up or down-regulated in mature adipocytes as compared to preadipocytes. Otherwise, 17 of these 799 miRNAs (2.1%) were correlated with anthropometrical (BMI) and/or metabolic (fasting glucose and/or triglycerides) parameters. We identified 11 miRNAs (1.4%) significantly deregulated in subcutaneous fat from obese subjects with and without DM-2. Interestingly, most of these changes were associated with miRNAs also significantly deregulated during adipocyte differentiation. Conclusions/Significance:The remarkable inverse miRNA profile revealed for human pre-adipocytes and mature adipocytes hints at a closely crosstalk between miRNAs and adipogenesis. Such candidates may represent biomarkers and therapeutic targets for obesity and obesity-related complications. © 2010 Ortega et al.


Fernandez-Real J.M.,University of Girona | Fernandez-Real J.M.,CIBER ISCIII | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Pickup J.C.,Guys Hospital
Diabetologia | Year: 2012

In this edition of 'Then and now' the initial studies by J.C. Pickup and colleagues supporting the hypothesis that type 2 diabetes is caused by activated innate immunity, published in Diabetologia in 1997 (40:1286-1292), are discussed. These initial findings led to research that has uncovered links between insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to the altered production or function of circulating innate immune proteins, cellular pattern recognition receptors and inflammatory cytokines are linked to obesity, insulin resistance and type 2 diabetes. Components of the innate immune system in the muscle, bone, liver and adipose tissue, as well as macrophages, have been revealed to play a role in systemic insulin action. Evolutionary pressures, such as acute infections at the population level (pandemics) and chronic low exposure to environmental products or infectious agents, may have contributed to increased susceptibility and to the current increase in the prevalence of insulin resistance and type 2 diabetes. © 2011 Springer-Verlag.


Ortega F.J.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Jilkova Z.M.,Academy of Sciences of the Czech Republic | Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Pavelka S.,Masaryk University | And 3 more authors.
International Journal of Obesity | Year: 2012

Differentiation and metabolism of adipose tissue are modulated by thyroid hormones (THs), but relatively little is known about the metabolism of THs in this tissue. Expression of the genes for type I iodothyronine 5′-deiodinase (D1), leptin (LEP) and stearoyl-CoA desaturase 1 (SCD-1) was evaluated in omental (OM) and subcutaneous (SC) fat using a cohort of 70 humans. Activities of iodothyronine deiodinases (D1, D2 and D3) were assessed in a randomly selected subpopulation of 19 subjects. D1 expression was upregulated in both OM (P=0.011) and SC (P=0.003) fat of obese subjects. Concomitantly, OM (P=0.002) and SC (P=0.028) LEP expression were increased in obesity, associated with both D1 mRNA (r=0.315, P=0.014) and activity (r=0.647, P=0.023) and inversely related to SCD-1 (r=-0.266, P=0.034) expression in SC fat. Also D1 (but not D2 and D3) activity was increased in OM (∼fourfold, P=0.010) and SC (∼eightfold, P=0.004) fat of obese when compared with non-obese subjects and correlated in both OM (r=0.528, P=0.036) and SC (r=0.749, P=0.005) fat with body mass index. Our results document increased D1 gene expression and activity in adipose tissue of obese humans and suggest a role of 3,5,3′-triiodo-L- thyronine formed by D1 in response to leptin in the modulation of adipose tissue metabolism. © 2012 Macmillan Publishers Limited All rights reserved.


Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Sabater M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Ortega F.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Ricart W.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi
PLoS ONE | Year: 2012

Zonulin is the only physiological mediator known to regulate intestinal permeability reversibly by modulating intercellular tight junctions. To investigate the relationship between intestinal permeability and obesity-associated metabolic disturbances in humans, we aimed to study circulating zonulin according to obesity and insulin resistance. Circulating zonulin (ELISA) was measured in 123 caucasian men in association with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity). Circulating zonulin increased with body mass index (BMI), waist to hip ratio (WHR), fasting insulin, fasting triglycerides, uric acid and IL-6, and negatively correlated with HDL-cholesterol and insulin sensitivity. In multiple regression analysis, insulin sensitivity (p = 0.002) contributed independently to circulating zonulin variance, after controlling for the effects of BMI, fasting triglycerides and age. When circulating IL-6 was added to this model, only BMI (p = 0.01) contributed independently to circulating zonulin variance. In conclusion, the relationship between insulin sensitivity and circulating zonulin might be mediated through the obesity-related circulating IL-6 increase. © 2012 Moreno-Navarrete et al.


Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Moreno M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Vidal M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Ortega F.,Institute Dinvestigacio Biomedica Of Girona Idibgi | And 2 more authors.
Obesity | Year: 2015

Objective To investigate the possible role of deleted in breast cancer 1 (DBC1) in adipocyte and adipose tissue inflammation. Methods In vitro knockdown experiments using shRNA-lentiviral particles were performed to investigate the effect of DBC1 on adipocyte inflammation, sirtuin 1 (Sirt1) activity, and the AMPK pathway. The relationship between DBC1 and inflammation in human adipose tissue also was examined in two independent cohorts. Results Dbc1 knockdown (KD) led to a significant reduction in the expression of inflammatory genes (Tnf, Il6, Stamp2, Lbp, and Mcp1) and pSer536NF-κB (p65)/NF-κB (p65) ratio in fully differentiated adipocytes. Of note, Dbc1 KD increased Sirt1 and AMPK activity in the early stage of adipocyte differentiation. In morbidly obese participants, DBC1 was positively correlated to TNF and senescence (TP53 and BAX) gene expression markers in both subcutaneous and visceral adipose tissues. Multivariate regression analysis revealed that senescence-related gene markers were the best predictors of adipose tissue DBC1 mRNA levels. Conclusions DBC1 induced the expression of nuclear factor kappa B (NF-κB)-regulated inflammatory cytokines in fully differentiated 3T3-L1 adipocytes, possibly through the inhibition of Sirt1 activity, being significantly associated with human adipose tissue senescence in morbidly obese subjects. © 2015 The Obesity Society.


Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi
Expert Review of Clinical Immunology | Year: 2014

Currently, obesity-associated metabolic disturbances are envisioned as chronic inflammatory processes, characterized by activation of both innate and adaptive immunity. Although the features of chronic inflammation in obese subjects are clearly defined, the signals and mechanisms that trigger chronic inflammation are not well understood. Recent studies suggest an imbalance in circulating antimicrobial proteins as a possible cause of obesity-associated metabolic disturbances and insulin resistance. This imbalance promotes a relative failure in the capacity of buffering external insults and might cause the onset of chronic inflammation and immunologic alterations in obesity. Here, we review the current literature on the possible role of circulating antimicrobial proteins in obesity-associated immunologic alterations. © 2014 Informa UK, Ltd.


Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Ortega F.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Moreno M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Serrano M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | And 2 more authors.
Journal of Cellular and Molecular Medicine | Year: 2014

In human and mice adipose tissue, lactoferrin (LTF) has been found to be associated with increased adipogenesis and decreased inflammatory markers. Here, we aimed to investigate the effects of LTF knockdown (KD) in human adipocyte differentiation. In addition, the effects of exogenous LTF administration and iron chelation [using deferoxamine (DFO, 10 μM)] were tested. In both subcutaneous and visceral pre-adipocytes, LTF KD led to decrease significantly adipogenic, lipogenic and insulin signalling-related gene expression and a significant increase in the gene expression of inflammatory mediators. Human lactoferrin (hLf, 1 μM) administration led to recover adipocyte differentiation in LTF KD pre-adipocytes. Interestingly, iron chelation triggered similar effects to LTF KD, decreasing significantly adipogenic gene expressions. Of note, DFO (10 μM) and hLf (1 and 10 μM) co-administration led to a dose-dependent recovery of adipocyte differentiation. These new data reveal that endogenous LTF biosynthesis during human adipocyte differentiation is essential to achieve this process, possibly, modulating adipocyte iron homoeostasis. hLf administration might be a useful therapeutic target in obesity-associated adipose tissue dysfunction. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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