RESUMEN
INTRODUCTION: This study aims to investigate if a mixture of functional lipids (FLs), containing conjugated linoleic acid (CLA), tocopherols (TPs), and phytosterols (PSs), prevents some lipid alterations induced by high-fat (HF) diets, without adverse effects. METHODS: Male CF1 mice (n = 6/group) were fed (4 weeks) with control (C), HF, or HF + FL diets. RESULTS: FL prevented the overweight induced by the HF diet and reduced the adipose tissue (AT) weight, associated with lower energy efficiency. After the intervention period, the serum triacylglycerol (TAG) levels in both HF diets underwent a decrease associated with an enhanced LPL activity (mainly in muscle). The beneficial effect of the FL mixture on body weight gain and AT weight might be attributed to the decreased lipogenesis, denoted by the lower mRNA levels of SREBP1-c and ACC in AT, as well as by an exacerbated lipid catabolism, reflected by increased mRNA levels of PPARα, ATGL, HSL, and UCP2 in AT. Liver TAG levels were reduced in the HF + FL group due to an elevated lipid oxidation associated with a higher CPT-1 activity and mRNA levels of PPARα and CPT-1a. Moreover, genes linked to fatty acid biosynthesis (SREBP1-c and ACC) showed decreased mRNA levels in both HF diets, this finding being more pronounced in the HF + FL group. CONCLUSION: The administration of an FL mixture (CLA + TP + PS) prevented some lipid alterations induced by a HF diet, avoiding frequent deleterious effects of CLA in mice through the modulation of gene expression related to the regulation of lipid metabolism.
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Dieta Alta en Grasa , Ácidos Linoleicos Conjugados , Metabolismo de los Lípidos , Hígado , PPAR alfa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Triglicéridos , Animales , Dieta Alta en Grasa/efectos adversos , Ratones , Masculino , Triglicéridos/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , PPAR alfa/metabolismo , PPAR alfa/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Ácidos Linoleicos Conjugados/farmacología , Lipogénesis/efectos de los fármacos , Carnitina O-Palmitoiltransferasa/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Proteína Desacopladora 2/metabolismo , Proteína Desacopladora 2/genética , Fitosteroles/farmacología , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacos , Aumento de Peso/efectos de los fármacos , Lipoproteína Lipasa/metabolismo , Lipoproteína Lipasa/genéticaRESUMEN
BACKGROUND: Acute myeloid leukemia (AML), one of the common malignancies of the hematologic system, has progressively increased in incidence. Aging is present in both normal tissues and the tumor microenvironment. However, the relationship between senescence and AML prognosis is still not elucidated. METHODS: In this study, RNA sequencing data of AML were obtained from TCGA, and prognostic prediction models were established by LASSO-Cox analysis. Differences in immune infiltration between the different risk groups were calculated using the CIBERSORT and ESTIMATE scoring methods. The KEGG and GO gene enrichment and GSEA enrichment were also used to enrich for differential pathways between the two groups. Subsequently, this study collected bone marrow samples from patients and healthy individuals to verify the differential expression of uncoupling protein 2 (UCP2) in different populations. Genipin, a UCP2 protein inhibitor, was also used to examine its effects on proliferation, cell cycle, and apoptosis in AML cell lines in vitro. RESULTS: It showed that aging-related genes (ARGs) expression was correlated with prognosis. And there was a significant difference in the abundance of immune microenvironment cells between the two groups of patients at high risk and low risk. Subsequently, UCP2 expression was found to be elevated in AML patients. Genipin inhibits UCP2 protein and suppresses the proliferation of AML cell lines in vitro. CONCLUSION: ARGs can be used as a predictor of prognosis in AML patients. Moreover, suppressing UCP2 can reduce the proliferation of AML cell lines, alter their cell cycle, and promote apoptosis in vitro.
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Leucemia Mieloide Aguda , Humanos , Proteína Desacopladora 2 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Pronóstico , Envejecimiento , Microambiente Tumoral/genéticaRESUMEN
Non-small cell lung cancer (NSCLC) accounts for the vast majority of cases of lung neoplasms. It is formed in multiple stages, with interactions between environmental risk factors and individual genetic susceptibility and with genes involved in the immune and inflammatory response paths, cell or genome stability, and metabolism, among others. Our objective was to evaluate the association between five genetic variants (IL-1A, NFKB1, PAR1, TP53, and UCP2) and the development of NSCLC in the Brazilian Amazon. The study included 263 individuals with and without lung cancer. The samples were analyzed for the genetic variants of NFKB1 (rs28362491), PAR1 (rs11267092), TP53 (rs17878362), IL-1A (rs3783553), and UCP2 (INDEL 45-bp), which were genotyped in PCR, followed by an analysis of the fragments, in which we applied a previously developed set of informative ancestral markers. We used a logistic regression model to identify differences in the allele and the genotypic frequencies among individuals and their association with NSCLC. The variables of gender, age, and smoking were controlled in the multivariate analysis to prevent confusion by association. The individuals that were homozygous for the Del/Del of polymorphism NFKB1 (rs28362491) (p = 0.018; OR = 0.332) demonstrate a significant association with NSCLC, which was similar to that observed in the variants of PAR1 (rs11267092) (p = 0.023; OR = 0.471) and TP53 (rs17878362) (p = 0.041; OR = 0.510). Moreover, the individuals with the Ins/Ins genotype of polymorphism IL-1A (rs3783553) demonstrated greater risk for NSCLC (p = 0.033; OR = 2.002), as did the volunteers with the Del/Del of UCP2 (INDEL 45-bp) (p = 0.031; OR = 2.031). The five polymorphisms investigated can contribute towards NSCLC susceptibility in the population of the Brazilian Amazon.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Subunidad p50 de NF-kappa B , Receptor PAR-1 , Proteína p53 Supresora de Tumor , Proteína Desacopladora 2 , Humanos , Brasil/epidemiología , Subunidad p50 de NF-kappa B/genética , Polimorfismo Genético , Receptor PAR-1/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Objective: To evaluate the expression of UCP1, UCP2, and UCP3 mRNA and encoded proteins in epicardial and mediastinal adipose tissues in patients with coronary artery disease (CAD). Subjects and methods: We studied 60 patients with CAD and 106 patients undergoing valve replacement surgery (controls). Expression levels of UCP1, UCP2, and UCP3 mRNA and encoded proteins were measured by quantitative real-time PCR and Western blot analysis, respectively. Results: : We found increased UCP1, UCP2, and UCP3 mRNA levels in the epicardial adipose tissue in the CAD versus the control group, and higher UCP1 and UCP3 mRNA expression in the epicardial compared with the mediastinal tissue in the CAD group. There was also increased expression of UCP1 protein in the epicardial tissue and UCP2 protein in the mediastinum tissue in patients with CAD. Finally, UCP1 expression was associated with levels of fasting plasma glucose, and UCP3 expression was associated with levels of high-density lipoprotein cholesterol and low-density cholesterol in the epicardial tissue. Conclusion: Our study supports the hypothesis that higher mRNA expression by UCP genes in the epicardial adipose tissue could be a protective mechanism against the production of reactive oxygen species and may guard the myocardium against damage. Thus, UCP levels are essential to maintain the adaptive phase of cardiac injury in the presence of metabolic disorders.
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Enfermedad de la Arteria Coronaria , Mediastino , Humanos , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Enfermedad de la Arteria Coronaria/genética , Canales Iónicos/genética , Canales Iónicos/metabolismo , Tejido Adiposo Pardo/química , Tejido Adiposo Pardo/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Tejido Adiposo/metabolismo , Colesterol , Proteína Desacopladora 3/genética , Proteína Desacopladora 3/metabolismo , Músculo Esquelético , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismoRESUMEN
El ambiente obesogénico promueve la obesidad al facilitar el acceso y consumo de una amplia variedad de alimentos palatables altos en calorías. La activación del receptor de GLP1 (GLP1R) reduce la ingesta de alimentos, enlentece el vaciamiento gástrico y promueve un balance energético negativo a través de su acción en distintos órganos como el músculo esquelético, disminuyendo así el peso corporal. La obesidad inducida por dieta alta en grasa disminuye el efecto anorexigénico de la administración sistémica vía intra-peritoneal de EX4 (agonista de GLP1R). Sin embargo, se desconoce si la exposición a un ambiente obesogénico previo a la manifestación de obesidad disminuye los efectos anorexigénicos de EX4 o un posible efecto de EX4 sobre marcadores de oxidación de ácidos grasos y termogénesis en músculo esquelético. El objetivo de esta investigación fue determinar el efecto a corto plazo de la dieta CAF, un modelo del ambiente obesogénico humano, sobre la capacidad de EX4 de reducir la ingesta y modular la expresión de marcadores proteicos de oxidación de ácidos grasos y termogénesis (CPT1 y UCP2) en músculo de ratones. Nuestros datos muestran que una inyección intraperitoneal de EX4 a ratones C57BL/6J alimentados con dieta CAF o dieta control durante 10 días no altera la ingesta calórica total, peso corporal, o la expresión de proteínas marcadoras de los procesos de beta-oxidación y de termogénesis (CPT1 y UCP2). Estos datos sugieren que protocolos alternativos de administración de EX4 son necesarios para observar los efectos fisiológicos de la activación de GLP1R.
The obesogenic environment promotes obesity by facilitating access to and consumption of a wide variety of palatable, high-calorie foods. Activation of the GLP1 receptor (GLP1R) reduces food intake, slows gastric emptying, and promotes a negative energy balance by acting on organs such as skeletal muscle, thus decreasing body weight. Obesity induced by a high-fat diet decreased the anorexigenic effect of intraperitoneal systemic administration of EX4 (GLP1R agonist). However, it is unknown whether exposure to an obesogenic environment before the manifestation of obesity diminishes the anorexigenic effects of EX4 or a possible effect of EX4 on markers of fatty acid oxidation and thermogenesis in skeletal muscle. This investigation aimed to determine the short-term effect of the CAF diet, a model of the human obesogenic environment, on the ability of EX4 to reduce intake and modulate the expression of protein markers of fatty acid oxidation and thermogenesis (CPT1 and UCP2) in mouse muscle. Our data show that intraperitoneal injection of EX4 to C57BL/6J mice fed CAF diet or control diet for ten days does not alter total caloric intake, body weight, or expression of proteins markers of beta-oxidation and thermogenesis processes (CPT1 and UCP2). These data suggest that alternative EX4 administration protocols are necessary to observe the physiological effects of GLP1R activation.
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Animales , Masculino , Ratones , Dieta/efectos adversos , Exenatida/administración & dosificación , Obesidad/etiología , Obesidad/metabolismo , Oxidación-Reducción , Western Blotting , Músculo Esquelético/metabolismo , Termogénesis , Ácidos Grasos/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Proteína Desacopladora 2 , Irinotecán , Inyecciones Intraperitoneales , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Uncoupling protein 2 (UCP2) plays an important role in energy expenditure regulation. Previous studies have associated the common -866G/A (rs659366) and Ins/Del polymorphisms in the UCP2 gene with metabolic and obesity-related phenotypes. However, it is still unclear whether these polymorphisms influence weight loss after bariatric surgery. OBJECTIVES: To investigate whether UCP2 -866G/A and Ins/Del polymorphisms are associated with weight loss outcomes after bariatric surgery. SETTING: Longitudinal study in a university hospital. METHODS: We retrospectively evaluated 186 patients who underwent Roux-en-Y gastric bypass (RYGB) surgery for clinical and laboratory characteristics in the preoperative period, 6, 12, and 18 months after RYGB. The -866G/A (rs659366) polymorphism was genotyped using real-time PCR, while the Ins/Del polymorphism was genotyped by direct separation of PCR products in 2.5% agarose gels. RESULTS: Patients with the -866A/A genotype showed higher body mass index (BMI) after 6, 12, and 18 months of surgery and excess body weight after 6 and 12 months compared with G/G patients. They also showed lower excess weight loss (EWL%) after 6 and 12 months of surgery. Ins allele carriers (Ins/Ins + Ins/Del) had lower delta (Δ) BMI 12 months after surgery compared with Del/Del patients. Accordingly, patients carrying haplotypes with ≥2 risk alleles of these polymorphisms had higher BMI and excess weight and lower EWL% during follow-up. CONCLUSION: UCP2 -866A/A genotype is associated with higher BMI and excess weight and lower EWL% during an 18-month follow-up of patients who underwent RYGB, while the Ins allele seems to be associated with lower ΔBMI 12 months after surgery. Further studies are needed to confirm the associations of the -866G/A and Ins/Del polymorphisms with weight loss after bariatric surgery.
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Derivación Gástrica , Obesidad Mórbida , Índice de Masa Corporal , Humanos , Canales Iónicos/genética , Estudios Longitudinales , Proteínas Mitocondriales/genética , Obesidad Mórbida/genética , Obesidad Mórbida/cirugía , Estudios Retrospectivos , Proteína Desacopladora 2/genética , Pérdida de Peso/genéticaRESUMEN
BACKGROUND: Bariatric surgery is currently the most effective treatment for patients with severe obesity. Uncoupling proteins (UCP) 1, 2, and 3 play key roles in the regulation of energy balance and weight. Previous studies have suggested that changes in UCP1-3 genes could influence weight loss after bariatric surgery. However, it is still unclear if these UCPs are indeed involved in weight loss variability after surgery. Therefore, we performed a systematic review aiming to summarize the results of studies on this subject. METHODS: A literature search was performed for all studies that evaluated associations of UCP1-3 expressions and their polymorphisms with obesity-related outcomes after bariatric surgery. RESULTS: Twenty-six studies were eligible for inclusion in this systematic review. Among them, 18 evaluated UCP1-3 expressions while 8 studies investigated the association between UCP1-3 polymorphisms and weight loss after bariatric surgery. In general, UCP2 and UCP3 expressions in adipose tissue and skeletal muscle seem to be affected by metabolic changes of bariatric surgery, which might be influenced by the surgery type. Data on UCP1 expression in adipose tissue is still inconclusive. Only few studies investigated the association between polymorphisms in UCP1-3 genes and weight loss after bariatric surgery, with contradictory results. CONCLUSION: Available studies suggest that changes caused by bariatric surgery could influence UCP2 and UCP3 expressions in adipose tissue and muscles, consequently affecting weight loss. However, because of the reduced number of studies, further studies are needed to confirm whether these UCPs and their polymorphisms are indeed involved in weight loss after bariatric surgery.
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Cirugía Bariátrica , Pérdida de Peso , Humanos , Canales Iónicos/genética , Proteínas Mitocondriales/genética , Músculo Esquelético , Proteína Desacopladora 1 , Proteína Desacopladora 2/genética , Proteína Desacopladora 3RESUMEN
Nutritional imbalance in early life may disrupt the hypothalamic control of energy homeostasis and increase the risk of metabolic disease. The hypothalamic serotonin (5-hydroxytryptamine; 5-HT) system based in the hypothalamus plays an important role in the homeostatic control of energy balance, however the mechanisms underlying the regulation of energy metabolism by 5-HT remain poorly described. Several crucial mitochondrial functions are altered by mitochondrial stress. Adaptations to this stress include changes in mitochondrial multiplication (i.e, mitochondrial biogenesis). Due to the scarcity of evidence regarding the effects of serotonin reuptake inhibitors (SSRI) such as fluoxetine (FLX) on mitochondrial function, we sought to investigate the potential contribution of FLX on changes in mitochondrial function and biogenesis occurring in overfed rats. Using a neonatal overfeeding model, male Wistar rats were divided into 4 groups between 39 and 59 days of age based on nutrition and FLX administration: normofed + vehicle (NV), normofed + FLX (NF), overfed + vehicle (OV) and overfed + FLX (OF). We found that neonatal overfeeding impaired mitochondrial respiration and increased oxidative stress biomarkers in the hypothalamus. FLX administration in overfed rats reestablished mitochondrial oxygen consumption, increased mitochondrial uncoupling protein 2 (Ucp2) expression, reduced total reactive species (RS) production and oxidative stress biomarkers, and up-regulated mitochondrial biogenesis-related genes. Taken together our results suggest that FLX administration in overfed rats improves mitochondrial respiratory chain activity and oxidative balance and increases the transcription of genes employed in mitochondrial biogenesis favoring mitochondrial energy efficiency in response to early nutritional imbalance.
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Fármacos Antiobesidad/farmacología , Metabolismo Energético/efectos de los fármacos , Fluoxetina/farmacología , Hipotálamo/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Biogénesis de Organelos , Hipernutrición/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Factores de Edad , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Animales Recién Nacidos , Animales Lactantes , Hipotálamo/metabolismo , Hipotálamo/patología , Hipotálamo/fisiopatología , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Estado Nutricional , Hipernutrición/metabolismo , Hipernutrición/patología , Hipernutrición/fisiopatología , Oxidación-Reducción , Consumo de Oxígeno , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Transcripción Genética , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismoRESUMEN
The aim of this study was to compare the expression of UCP2, NLRP3, IL1B, IL18, and miR-133a-3p in subcutaneous adipose tissue (SAT) of 61 patients divided according to BMI: Group 1 (n = 8; BMI<25.0 kg/m2), Group 2 (n = 24; BMI 30.0-39.9 kg/m2), and Group 3 (n = 29; BMI≥40.0 kg/m2). SAT biopsies were obtained from individuals who underwent bariatric surgery or elective abdominal surgery. Gene expressions were quantified using qPCR. Bioinformatics analyses were employed to investigate target genes and pathways related to miR-133a-3p. UCP2 and miR-133a-3p expressions were decreased in SAT of Groups 2 and 3 while IL18 was increased compared to Group 1. NLRP3 and IL1B expressions did not differ between groups; however, NLRP3 was positively correlated with waist circumference and excess weight. Bioinformatics analysis demonstrated that UCP2 and NLRP3 are targets of miR-133a-3p. In conclusion, UCP2 and miR-133a-3p expressions are downregulated in patients with obesity, while IL18 is upregulated. NRLP3 is correlated with waist circumference and weight excess.
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Regulación de la Expresión Génica , Interleucina-18/metabolismo , MicroARNs/metabolismo , Obesidad/genética , Grasa Subcutánea/metabolismo , Proteína Desacopladora 2/metabolismo , Adulto , Índice de Masa Corporal , Femenino , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , MicroARNs/genética , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal/genética , Proteína Desacopladora 2/genéticaRESUMEN
The mitochondrial uncoupling protein 2 (UCP2) decreases reactive oxygen species (ROS) formation by mitochondria. Our group previously showed that the UCP2 -866A allele was associated with risk of diabetic retinopathy (DR), which is caused by hyperglycemia-induced oxidative stress. To date, it is still unclear if the -866A allele directly affects UCP2 expression in endothelial cells. Thus, we investigated the effect of the A allele on UCP2 promoter activity in HUVECs treated with high glucose (HG) or hydrogen peroxide (H2O2). To quantify UCP2 promoter activity, HUVECs were transfected with pGL3 plasmids containing the UCP2 promoter and the firefly luciferase coding sequence. Experimental groups were: (1) pGL3-866G-transfected cells and (2) pGL3-866A cells, both under normal (4 mM) or HG (25 mM) concentrations for 24 h and 48 h or incubated with H2O2 (0.1 mM) for 1 h. UCP2 promoter activity was monitored by Luminescent Dual-luciferase Assay. HG induced an upregulation of UCP2 promoter activity in PGL3-866G cells after 24 h of treatment (P = 0.027), but not after 48 h. Compared to pGL3-866G cells, pGL3-866A cells seems to have reduced UCP2 promoter activity following 24 h and 48 h of normal glucose treatment (P = 0.087 and P = 0.022). After HG treatment, pGL3-866A cells had more marked UCP2 downregulation (24 h: - 3.2-folds, P < 0.001; and 48 h: - 2.5-folds, P < 0.001 vs. G cells). Both pGL3-866G and pGL3-866A cells treated with H2O2 showed a â 4-fold increase in UCP2 promoter activity (both P < 0.001). The -866A allele modifies UCP2 promoter activity in HUVECs under HG treatment but not in the H2O2 condition.
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Alelos , Genotipo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Proteína Desacopladora 2/genética , Genes Reporteros , Glucosa/metabolismo , Glucosa/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Estrés OxidativoRESUMEN
Neuroprotection is a desirable process in many neurological disorders, yet complex mechanisms involved in this field are not completely understood. The pilocarpine epilepsy model causes potent, seizure-induced excitotoxicity cell death and mitochondria impairment. The present study is aimed at investigating the role of UCP2, a ROS negative regulator, in the neuroprotection after cholinergic insult. Our data demonstrated that UCP2 expression was augmented in the rat hippocampus 3 days after status epilepticus (SE), reaching a peak on the fifth day, then returning to basal levels. Concomitantly, phospho-AKT expression levels were higher in the hippocampus during the early silent phase (5 days after SE). Additionally, it was demonstrated that the blockade of UCP2 by antisense oligonucleotides (ASO) in SE rats successfully diminished both UCP2 mRNA and protein contents. SE ASO rats presented increased mitochondrial proapoptotic factor expression, caspase-3 activity, inflammatory cytokine expression, and ROS formation. Moreover, ASO treatment diminished p-AKT expression and antioxidant enzyme activities after pilocarpine insult. In conclusion, the present results highlight the neuroprotective actions of UCP2, acting in the inhibition of apoptotic factors and oxidative stress, to increase neuron survival after SE onset.
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Estrés Oxidativo/fisiología , Estado Epiléptico/inducido químicamente , Estado Epiléptico/metabolismo , Proteína Desacopladora 2/metabolismo , Animales , Apoptosis/fisiología , Modelos Animales de Enfermedad , Masculino , Estrés Oxidativo/efectos de los fármacos , Pilocarpina , Ratas , Ratas Wistar , Estado Epiléptico/patologíaRESUMEN
This work aims to assess the possible beneficial effects of dietary fish oil (FO) on the pre-existing adipose tissue dysfunction through the improvement or reversion of the mechanisms underlying oxidative stress and pro-inflammatory cytokines in dyslipemic insulin-resistant rats. Wistar rats were fed a sucrose rich diet (SRD) for 6 months. After that half of the animals continued with the SRD until month 8 while in the other half corn oil was replaced by FO for 2 months (SRD + FO). A reference group consumed a control diet all the time. In an epididymal fat pad, we analyzed antioxidant and oxidant enzyme activities, ROS content, glutathione redox state, the protein level of peroxisome proliferator-activated receptor gamma (PPARγ) and the expression and protein levels of uncoupling protein 2 (UCP2) as well as oxidative stress biomarkers and TNF-α and IL-6 plasma levels. Besides these, insulin sensitivity and the composition of fatty acid phospholipids of adipose tissue were measured. Compared with the SRD the SRD + FO fed group showed a decrease of fat pad weight and the antioxidant and oxidant enzyme activities and ROS content returned to control values along with normal plasma TNF-α and IL-6 levels. FO normalized both the decrease of PPARγ protein and the increase of protein and expression of UCP2. Furthermore, FO increased the n-3/n-6 fatty acid ratio in the adipose tissue phospholipids and normalized dyslipidemia and insulin resistance. Finally, these findings reinforce the view that dietary FO may exert a beneficial effect in ameliorating the dyslipidemia and insulin resistance in this animal model.
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Sacarosa en la Dieta/efectos adversos , Dislipidemias/dietoterapia , Aceites de Pescado/metabolismo , Resistencia a la Insulina , Estrés Oxidativo , PPAR gamma/metabolismo , Proteína Desacopladora 2/metabolismo , Tejido Adiposo/metabolismo , Animales , Sacarosa en la Dieta/metabolismo , Dislipidemias/etiología , Dislipidemias/genética , Dislipidemias/metabolismo , Glutatión/metabolismo , Humanos , Insulina/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , PPAR gamma/genética , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Proteína Desacopladora 2/genéticaRESUMEN
BACKGROUND: It has been reported that the uncoupling proteins (UCPs) can contribute to energy metabolism, and are thus involved in the pathogenesis of obesity. The objective of the study was to analyze the association between UCP polymorphisms, clinical parameters and leptin and adiponectin plasma levels in an adolescent population with overweight and obesity. METHODS: We analyzed the UCP1 -3826 C/T, UCP2-866 G/A, Ala55Val and UCP3 -55 C/T polymorphisms and the levels of adipokines in adolescents with normal weight and with overweight or obesity. The study included 270 students aged between 12 and 18 years categorized according to the percentiles from Mexico City. Adipokines levels were measured by immunoassay methods and the UCP polymorphisms were determined using Taqman real-time polymerase chain reaction (RT-PCR). RESULTS: No significant differences were found in the UCP polymorphisms in seven inheritance models studied. Most of the significant differences in the clinical parameters were found under a recessive model, the UCP2 -866 polymorphism was associated with diastolic blood pressure (p=0.008), triglycerides (p=0.045), low-density lipoprotein-cholesterol (LDL-C) (p=0.003), high-density lipoprotein-cholesterol (HDL-C) (p=0.050) and plasma levels of leptin (p<0.001). Also, the obese group was found to have higher leptin levels and lower adiponectin levels in GA+AA vs. GG (recessive model). CONCLUSIONS: This study demonstrated a direct relationship between the clinical characteristics and UCP2-866 in a recessive model, associated with high levels of leptin and decreased levels of adiponectin in an obese or overweight Mexican adolescent population.
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Adipoquinas/sangre , Obesidad/sangre , Sobrepeso/sangre , Polimorfismo de Nucleótido Simple , Proteína Desacopladora 1/sangre , Proteína Desacopladora 2/sangre , Proteína Desacopladora 3/sangre , Adolescente , Biomarcadores/análisis , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Leptina/sangre , Masculino , México/epidemiología , Obesidad/diagnóstico , Obesidad/epidemiología , Sobrepeso/diagnóstico , Sobrepeso/epidemiología , Pronóstico , Proteína Desacopladora 1/genética , Proteína Desacopladora 2/genética , Proteína Desacopladora 3/genéticaRESUMEN
OBJECTIVE: The aim of this study was to investigate whether the Ala55Val and -866G>A polymorphisms of the UCP2 gene are related to weight loss and changes in body composition after bariatric surgery performed by Roux-en-Y gastric bypass (RYGB). METHODS: This longitudinal study enrolled obese patients submitted to RYGB. Data regarding weight (kg), body mass index (kg/m2), fat-free mass (FFM; kg), fat mass (kg), weight loss (kg and %), and percent excess weight loss were collected from both preoperative and 1-y postoperative medical records. Polymorphisms were genotyped by allelic discrimination using real-time polymerase chain reaction and TaqMan-predesigned single nucleotide polymorphism Genotyping Assay kits (Applied Biosystems, Foster City, CA, USA). The t test was used to compare variables between genotypes of each polymorphism to analyze the dominant and recessive models. Linear regression models were used to adjust the effects of initial weight, age, and sex on the variation of weight and body composition (P < 0.05). RESULTS: We analyzed 150 severely obese individuals (age 47.2 ± 10.5 y; 80% women). Genotype analysis showed a greater prevalence of heterozygous GA (41.3%) for -866G>A polymorphism and CT (39.3%) for Ala55Val polymorphism. Individuals who carried the T (CT+TT) and A (GA+AA) mutated alleles for Ala55Val and -866G>A, respectively, showed a higher weight and FFM loss. CONCLUSION: The mutated alleles T for Ala55Val and A for -866G>A polymorphism could be biomarkers of weight loss 1 y after RYGB.
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Derivación Gástrica , Mutación Missense , Obesidad Mórbida/cirugía , Polimorfismo de Nucleótido Simple , Proteína Desacopladora 2/genética , Adulto , Alelos , Sustitución de Aminoácidos , Biomarcadores , Composición Corporal , Índice de Masa Corporal , Brasil , Terapia Combinada , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Obesidad Mórbida/genética , Obesidad Mórbida/metabolismo , Obesidad Mórbida/terapia , Proteína Desacopladora 2/metabolismo , Pérdida de PesoRESUMEN
BACKGROUND/OBJECTIVES: Although energy restriction contributes to weight loss, it may also reduce energy expenditure, limiting the success of weight loss in the long term. Studies have described how genetics contributes to the development of obesity, and uncoupling proteins 1 and 2 (UCP1 and UCP2) and beta-3-adrenoceptor (ADRB3) have been implicated in the metabolic pathways that culminate in this condition. This study aimed to evaluate how the UCP1, UCP2 and ADRB3 genes influence weight loss in severely obese women submitted to hypocaloric dietary intervention. SUBJECTS/METHODS: This longitudinal study included 21 women divided into two groups: Group 1 (Dietary intervention (G1)) consisted of 11 individuals with severe obesity (body mass index (BMI) ⩾40 kg/m2), selected for dietary intervention and Group 2 (Control (G2)) consisted of 10 normal-weight women (BMI between 18.5 and 24.9 kg/m2). Evaluation included weight (kg), height (m), waist circumference (cm), body composition, resting metabolic rate (RMR, kcal) and abdominal subcutaneous adipose tissue collection. The dietary intervention required that G1 patients remained hospitalized in the university hospital for 6 weeks receiving a hypocaloric diet (1200 kcal per day). The statistical analyses included t-test for paired samples, Spearman correlation and multivariate linear regressions, with the level of significance set at P<0.05. RESULTS: Weight (155.0±31.4-146.5±27.8 kg), BMI (58.5±10.5-55.3±9.2 kg/m2), fat-free mass (65.4±8.6-63.1±7.1 kg), fat mass (89.5±23.0-83.4±21.0 kg) and RMR (2511.6±386.1-2324.0±416.4 kcal per day) decreased significantly after dietary intervention. Multiple regression analyses showed that UCP2 expression contributed to weight loss after dietary intervention (P=0.05). CONCLUSIONS: UCP2 expression is associated with weight loss after hypocaloric diet intervention.
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Dieta Reductora , Proteína Desacopladora 2/metabolismo , Pérdida de Peso/genética , Adulto , Metabolismo Basal , Composición Corporal , Índice de Masa Corporal , Femenino , Regulación de la Expresión Génica , Humanos , Modelos Lineales , Estudios Longitudinales , Persona de Mediana Edad , Análisis Multivariante , Obesidad/genética , Obesidad Mórbida/genética , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 2/genética , Circunferencia de la Cintura , Adulto JovenRESUMEN
BACKGROUND: Analysis of the expression of genes related to the energy metabolism can elucidate the understanding of physiological and genetic factors that contribute to obesity. This study aimed to evaluate the expression of genes and its influence on resting metabolic rate and weight loss in obese patients before and after bariatric surgery. METHODS: This study was conducted on 23 women, who were divided into two groups: bariatric surgery (preoperative and 6 months after surgery) and control. Abdominal subcutaneous adipose tissue samples were collected to analyze the gene expression, and the resting metabolic rate (RMR) was measured by indirect calorimetry. RESULTS: Significant differences were observed in weight reduction (22 %, p = 0.01), BMI (22.5 %, p = 0.01), and RMR values (10.5 %, p = 0.01) after the bariatric surgery, while the weight-adjusted RMR increased (15.8 %, p = 0.01). Increased UCP2 expression after 6 months of Roux-en-Y gastric bypass (RYGB) as compared to preoperative period (0.764 to 1.268, p = 0.01) was observed. Analysis with weight-adjusted RMR as dependent variable revealed that UCP2 (r 2 = 0.517, p = 0.01) and PLIN1 (r 2 = 0.420, p = 0.04) expression determine the RMR values in preoperative period. Moreover, UCP2 and PLIN1 expression in preoperative period influenced the percentage of weight loss, even when adjusted for age and BMI. CONCLUSIONS: We have demonstrated that after 6 months of bariatric surgery, there is significant increase in the UCP2 expression. Additionally, the expression of UCP2 and PLIN1 genes influences the resting metabolic rate in obese individuals and could predict the weight loss after bariatric surgery.
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Metabolismo Basal/genética , Obesidad Mórbida/genética , Perilipina-1/genética , Proteína Desacopladora 2/genética , Pérdida de Peso/genética , Adulto , Cirugía Bariátrica , Estudios de Casos y Controles , Metabolismo Energético/genética , Femenino , Humanos , Persona de Mediana Edad , Obesidad Mórbida/metabolismo , Obesidad Mórbida/cirugía , Perilipina-1/metabolismo , Periodo Preoperatorio , Grasa Subcutánea/metabolismo , Resultado del Tratamiento , Proteína Desacopladora 2/metabolismo , Adulto JovenRESUMEN
Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier superfamily involved in the control of body temperature and energy balance regulation. They are currently proposed as therapeutic targets for treating obesity and metabolic syndrome (MetS). We studied the gene expression regulation of UCP1, -2, and -3 in abdominal white adipose tissue (WAT) from control and MetS rats treated with two doses of a commercial mixture of resveratrol (RSV) and quercetin (QRC). We found that UCP2 was the predominantly expressed isoform, UCP3 was present at very low levels, and UCP1 was undetectable. The treatment with RSV + QRC did not modify UCP3 levels; however, it significantly increased UCP2 mRNA in control and MetS rats in association with an increase in oleic and linoleic fatty acids. WAT from MetS rats showed a significantly increased expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ when compared to the control group. Furthermore, PPAR-α protein levels were increased by the highest dose of RSV + QRC in the control and MetS groups. PPAR-γ expression was only increased in the control group. We conclude that the RSV + QRC treatment leads to overexpression of UCP2, which is associated with an increase in MUFA and PUFA, which might increase PPAR-α expression.
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Tejido Adiposo Blanco/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Síndrome Metabólico/tratamiento farmacológico , Proteínas Desacopladoras Mitocondriales/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Quercetina/uso terapéutico , Estilbenos/uso terapéutico , Animales , Insulina/sangre , Ácido Linoleico/metabolismo , Masculino , Síndrome Metabólico/patología , Síndrome Metabólico/veterinaria , Proteínas Desacopladoras Mitocondriales/metabolismo , Ácido Oléico/metabolismo , ARN Mensajero/metabolismo , Radioinmunoensayo , Ratas , Ratas Wistar , Resveratrol , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo , Proteína Desacopladora 3/genética , Proteína Desacopladora 3/metabolismoRESUMEN
Uncoupling protein 2 ( UCP2 ) plays an important role in body weight and energy metabolism and may be related to the control of food consumption. This study aimed to investigate the contribution of UCP2 gene variants on the dietary intake on a population after bariatric surgery. This study enrolled 150 obese patients (body mass index ≥ 35kg m(-2) ) who submitted to Roux-en-Y gastric bypass. Weight (kg), BMI (kg m(-2) ), energy (kcal d(-1) ) and macronutrients intake (g d(-1) ) of preoperative and 1-year postoperative period were collected from medical records. Ala55Val and -866G>A polymorphisms in the UCP2 gene were genotyped through allelic discrimination method in real-time polymerase chain reaction using the TaqMan pre-designed SNP Genotyping Assays kits. Hardy-Weinberg equilibrium, t-test and regression models were performed in statistical analysis (P<0.05).We found an allelic frequency of 0.44 for allele Val and 0.41 for allele A. In the postoperative period, patients with at least one rare allele for polymorphisms and with at least one rare allele for both polymorphisms together (haplotype) present a greater energy and carbohydrate intake, even after adjusting for gender, age and weight. Genetic variants in UCP2 gene were associated with the dietary consumption after Roux-En-Y gastric bypass.
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Cirugía Bariátrica , Dieta Reductora , Obesidad Mórbida/dietoterapia , Obesidad Mórbida/cirugía , Cooperación del Paciente , Polimorfismo de Nucleótido Simple , Proteína Desacopladora 2/genética , Adulto , Alelos , Regulación del Apetito , Índice de Masa Corporal , Brasil , Terapia Combinada , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Estudios Longitudinales , Masculino , Obesidad Mórbida/metabolismo , Regiones Promotoras Genéticas , Estudios Retrospectivos , Respuesta de Saciedad , Proteína Desacopladora 2/metabolismo , Pérdida de PesoRESUMEN
Sepsis is characterized by inflammatory and metabolic alterations, which lead to massive cytokine production, oxidative stress and organ dysfunction. In severe systemic inflammatory response syndrome, plasma non-esterified fatty acids (NEFA) are increased. Several NEFA are deleterious to cells, activate Toll-like receptors and inhibit Na+/K+-ATPase, causing lung injury. A Mediterranean diet rich in olive oil is beneficial. The main component of olive oil is omega-9 oleic acid (OA), a monounsaturated fatty acid (MUFA). We analyzed the effect of OA supplementation on sepsis. OA ameliorated clinical symptoms, increased the survival rate, prevented liver and kidney injury and decreased NEFA plasma levels in mice subjected to cecal ligation and puncture (CLP). OA did not alter food intake and weight gain but diminished reactive oxygen species (ROS) production and NEFA plasma levels. Carnitine palmitoyltransferase IA (CPT1A) mRNA levels were increased, while uncoupling protein 2 (UCP2) liver expression was enhanced in mice treated with OA. OA also inhibited the decrease in 5' AMP-activated protein kinase (AMPK) expression and increased the enzyme expression in the liver of OA-treated mice compared to septic animals. We showed that OA pretreatment decreased NEFA concentration and increased CPT1A and UCP2 and AMPK levels, decreasing ROS production. We suggest that OA has a beneficial role in sepsis by decreasing metabolic dysfunction, supporting the benefits of diets high in monounsaturated fatty acids (MUFA).
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Ácidos Grasos/metabolismo , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Ácido Oléico/farmacología , Sepsis/fisiopatología , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Western Blotting , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Ácidos Grasos Monoinsaturados/farmacología , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/metabolismo , Expresión Génica/efectos de los fármacos , Canales Iónicos/genética , Canales Iónicos/metabolismo , Riñón/metabolismo , Riñón/fisiopatología , Hígado/metabolismo , Hígado/fisiopatología , Masculino , Malondialdehído/metabolismo , Ratones , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Oxidación-Reducción/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sepsis/metabolismo , Sepsis/mortalidad , Análisis de Supervivencia , Tasa de Supervivencia , Proteína Desacopladora 2RESUMEN
INTRODUCTION: Uncoupling protein 2 (UCP2) reduces production of reactive oxygen species (ROS) by mitochondria. ROS overproduction is one of the major contributors to the pathogenesis of chronic diabetic complications, such as diabetic kidney disease (DKD). Thus, deleterious polymorphisms in the UCP2 gene are candidate risk factors for DKD. In this study, we investigated whether UCP2 -866G/A, Ala55Val and Ins/Del polymorphisms were associated with DKD in patients with type 2 diabetes mellitus (T2DM), and whether they had an effect on UCP2 gene expression in human kidney tissue biopsies. MATERIALS AND METHODS: In a case-control study, frequencies of the UCP2 -866G/A, Ala55Val and Ins/Del polymorphisms as well as frequencies of the haplotypes constituted by them were analyzed in 287 T2DM patients with DKD and 281 T2DM patients without this complication. In a cross-sectional study, UCP2 gene expression was evaluated in 42 kidney biopsy samples stratified according to the presence of the UCP2 mutated -866A/55Val/Ins haplotype. RESULTS: In the T2DM group, multivariate logistic regression analysis showed that the -866A/55Val/Ins haplotype was an independent risk factor for DKD (OR = 2.136, 95% CI 1.036-4.404), although neither genotype nor allele frequencies of the individual polymorphisms differed between case and control groups. Interestingly, T2DM patients carrying the mutated haplotype showed decreased estimated glomerular filtration rate (eGFR) when compared to subjects with the reference haplotype (adjusted P= 0.035). In kidney biopsy samples, UCP2 expression was significantly decreased in UCP2 mutated haplotype carriers when compared to kidneys from patients with the reference haplotype (0.32 ± 1.20 vs. 1.85 ± 1.16 n fold change; adjusted P< 0.000001). DISCUSSION: Data reported here suggest that the UCP2 -866A/55Val/Ins haplotype is associated with an increased risk for DKD and with a lower eGFR in T2DM patients. Furthermore, this mutated haplotype was associated with decreased UCP2 gene expression in human kidneys.