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It is known that the inflammation process leading to oxidative stress and thyroid hormone metabolism dysfunction is highly altered in metabolic dysfunction associated with steatotic liver disease (MASLD). This study aims to address the effect of ornithine aspartate (LOLA) and vitamin E (VitE) in improving these processes. Adult Sprague-Dawley rats were assigned to five groups and treated for 28 weeks: controls (n = 10) received a standard diet (for 28 weeks) plus gavage with distilled water (DW) from weeks 16 to 28. MASLD groups received a high-fat and choline-deficient diet for 28 weeks (MASLD group) and daily gavage with 200 mg/kg/day of LOLA, or twice a week with 150 mg of VitE from weeks 16-28. LOLA diminished collagen deposition (p = 0.006). The same treatment diminished carbonyl, TBARS, and sulfhydryl levels and GPx activity (p < 0.001). Type 3 deiodinase increased in the MASLD group, downregulating T3-controlled genes, which was corrected in the presence of LOLA. LOLA also promoted a near-normalization of complex II, SDH, and GDH activities (p < 0.001) and improved reticulum stress, with a reduction in GRP78 and HSPA9/GRP75 protein levels (p < 0.05). The enhanced energy production and metabolism of thyroid hormones, probably because of GSH replenishment provided by the L-glutamate portion of LOLA, opens a new therapeutic approach for MASLD.
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Estrés Oxidativo , Ratas Sprague-Dawley , Vitamina E , Animales , Ratas , Vitamina E/farmacología , Vitamina E/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Hormonas Tiroideas/metabolismo , DipéptidosRESUMEN
Metabolic dysfunction-associated fatty liver disease (MAFLD) has gained worldwide attention as a public health problem. Nonetheless, lack of enough mechanistic knowledge restrains effective treatments. It is known that thyroid hormone triiodothyronine (T3) regulates hepatic lipid metabolism, and mitochondrial function. Liver dysfunction of type 3 deiodinase (D3) contributes to MAFLD, but its role is not fully understood. OBJECTIVE: To evaluate the role of D3 in the progression of MAFLD in an animal model. METHODOLOGY: Male/adult Sprague Dawley rats (n = 20) were allocated to a control group (2.93 kcal/g) and high-fat diet group (4.3 kcal/g). Euthanasia took place on the 28th week. D3 activity and expression, Uncoupling Protein 2 (UCP2) and type 1 deiodinase (D1) expression, oxidative stress status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured. RESULTS: We observed an increase in D3 activity/expression (p < 0.001) related to increased thiobarbituric acid reactive substances (TBARS) and carbonyls and diminished reduced glutathione (GSH) in the MAFLD group (p < 0.05). There was a D3-dependent decrease in UCP2 expression (p = 0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group (p < 0.001). Surprisingly, in an environment with lower T3 levels due to high D3 activity, we observed an augmented alpha-ketoglutarate dehydrogenase (KGDH) and glutamate dehydrogenase (GDH) enzymes activity (p < 0.05). CONCLUSION: Induced D3, triggered by changes in the REDOX state, decreases T3 availability and hepatic mitochondrial capacity. The Krebs cycle enzymes were altered as well as endoplasmic reticulum stress. Taken together, these results shed new light on the role of D3 metabolism in MAFLD.
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Yoduro Peroxidasa , Enfermedad del Hígado Graso no Alcohólico , Ratas , Animales , Masculino , Yoduro Peroxidasa/metabolismo , Ratas Sprague-Dawley , Hormonas Tiroideas/metabolismo , Triyodotironina/metabolismoRESUMEN
Low T3 syndrome occurs frequently in patients with sepsis. Type 3 deiodinase (DIO3) is present in immune cells, but there is no description of its presence in patients with sepsis. Here, we aimed to determine the prognostic impact of thyroid hormones levels (TH), measured on ICU admission, on mortality and evolution to chronic critical illness (CCI) and the presence of DIO3 in white cells. We used a prospective cohort study with a follow-up for 28 days or deceased. Low T3 levels at admission were present in 86.5% of the patients. DIO3 was induced by 55% of blood immune cells. The cutoff value of 60 pg/mL for T3 displayed a sensitivity of 81% and specificity of 64% for predicting death, with an odds ratio of 4.89. Lower T3 yielded an area under the receiver operating characteristic curve of 0.76 for mortality and 0.75 for evolution to CCI, thus displaying better performance than commonly used prognostic scores. The high expression of DIO3 in white cells provides a novel mechanism to explain the reduction in T3 levels in sepsis patients. Further, low T3 levels independently predict progression to CCI and mortality within 28 days for sepsis and septic shock patients.
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Yoduro Peroxidasa , Estrés Oxidativo , Choque Séptico , Triyodotironina , Humanos , Yoduro Peroxidasa/sangre , Estudios Prospectivos , Curva ROC , Choque Séptico/sangre , Choque Séptico/mortalidad , Triyodotironina/sangreRESUMEN
The Thr92Ala-Dio2 polymorphism has been associated with reduced cognition in 2-month-old male mice and increased risk for cognitive impairment and Alzheimer's disease in African Americans. This has been attributed to reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress in the brain. Here we studied the Thr92Ala-Dio2 mouse model and saw that older male mice (7-8-month-old) exhibited a more severe cognition impairment, which extended to different aspects of declarative and working memories. A similar phenotype was observed in 4-5-month-old female mice. There were no structural alterations in the prefrontal cortex (PFC) and hippocampus of the Thr92Ala-Dio2 mouse. Nonetheless, in both male and female PFC, there was an enrichment in genes associated with TH-dependent processes, ER stress, and Golgi apparatus, while in the hippocampus there was additional enrichment in genes associated with inflammation and apoptosis. Reduced TH signaling remains a key mechanism of disease given that short-term treatment with L-T3 rescued the cognitive phenotype observed in males and females. We conclude that in mice, age is an additional risk factor for cognitive impairment associated with the Thr92Ala-Dio2 polymorphism. In addition to reduced TH signaling, ER-stress, and involvement of the Golgi apparatus, hippocampal inflammation and apoptosis were identified as potentially important mechanisms of a disease.
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Background: Type 2 Deiodinase (DIO2) converts thyroxine (T4) into the active hormone triiodothyronine (T3). Thr92Ala DIO2 polymorphism has been associated with reduced conversion of T4 into T3 and central nervous system hypothyroidism. However, how Thr92Ala DIO2 polymorphism affects cognitive function is still unclear. Objective: To assess the association between Thr92Ala DIO2 polymorphism and cognitive performance in older adults. Design: Cross-sectional study. Setting: University-based tertiary hospital in Brazil. Patients: > 65-year-old with no limiting clinical disease. Interventions: All participants answered a standard questionnaire before undergoing thyroid function laboratory evaluation and genotyping of the Thr92Ala DIO2 polymorphism. Main Outcomes: Cognitive impairment measured by the Word List Memory task from the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) and the Brief Cognitive Screening Battery (BCSB). Results: A hundred individuals were included. Clinical and laboratory characteristics were similar among DIO2 genotypes (all p > 0.05). No differences were found in the Word List Memory, recall, or recognition tests of the CERAD-NB assuming a recessive model for the Ala/Ala vs. Thr/Ala-Thr/Thr genotypes. Results of Clock Drawing Test, Animal Fluency Test, Mini-Mental State Exam, and Figure Memory Test of the BCSB were similar between groups. Conclusions: These findings suggest that Thr92Ala DIO2 polymorphism is not associated with relevant cognitive impairment in older adults.
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Thyroid hormone (TH) signaling controls muscle progenitor cells differentiation. However, inflammation can alter muscle TH signaling by modulating the expression of TH transporters (Slc16a2), receptors (Thra1), and deiodinase enzymes (Dio2 and Dio3). Thus, a proinflammatory environment could affect myogenesis. The role of a low-grade inflammatory milieu in TH signaling during myogenesis needs further investigation. Herein, we aimed to study the impact of the bacterial lipopolysaccharide (LPS)-induced inflammatory stimulus on the TH signaling during myogenesis. C2C12 myoblasts differentiation was induced without (CTR) or with 10 ng/mL LPS presence. The myoblasts under LPS stimulus release the proinflammatory cytokines (IL-6 and IL-1ß) and chemokines (CCL2 and CXCL-1). LPS decreases Myod1 expression by 28% during the initial myogenesis, thus reducing the myogenic stimulus. At the same time, LPS reduced the expression of Dio2 by 41% but doubled the D2 enzymatic activity. The late differentiation was not affected by inflammatory milieu, which only increased the Slc16a2 gene expression by 38%. LPS altered the intracellular metabolism of TH and reduced the initial myogenic stimulus. However, it did not affect late differentiation. Increased intracellular TH activation may be the compensatory pathway involved in the recovery of myogenic differentiation under a low-grade inflammatory milieu.
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CONTEXT: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and pulmonary fibrosis. OBJECTIVE: Our objectives were to evaluate were cumulative mortality during admission according to Thr92Ala-DIO2 polymorphism. METHODS: Here we conducted an observational, longitudinal, and prospective cohort study to investigate a possible association between the Thr92Ala-DIO2 polymorphism and intrahospital mortality from COVID-19 in adult patients admitted between June and August 2020. Blood biochemistry, thyroid function tests, length of stay, comorbidities, complications, and severity scores were also studied according to Thr92Ala-DIO2 polymorphism. RESULTS: In total, 220 consecutive patients (median age 62; 48-74 years) were stratified into 3 subgroups: Thr/Thr (nâ =â 79), Thr/Ala (nâ =â 119), and Ala/Ala (nâ =â 23). While the overall mortality was 17.3%, the lethality was lower in Ala/Thr patients (12.6%) than in Thr/Thr patients (21.7%) or Ala/Ala patients (23%). The heterozygous genotype (Thr/Ala) was associated with a 47% reduced risk of intrahospital mortality whereas univariate and multivariate logistic regression adjusted for multiple covariates revealed a reduction that ranged from 51% to 66%. The association of the Thr/Ala genotype with better clinical outcomes was confirmed in a metanalysis of 5 studies, including the present one. CONCLUSION: Here we provide evidence for a protective role played by Thr92Ala-DIO2 heterozygosity in patients with COVID-19. This protective effect follows an inheritance model known as overdominance, in which the phenotype of the heterozygote lies outside the phenotypical range of both homozygous.
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COVID-19 , Yoduro Peroxidasa , COVID-19/genética , COVID-19/mortalidad , Heterocigoto , Mortalidad Hospitalaria , Humanos , Yoduro Peroxidasa/genética , Estudios Longitudinales , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Yodotironina Deyodinasa Tipo IIRESUMEN
The increasing incidence of metabolic diseases is in part due to the high fructose consumption, a carbohydrate vastly used in industry, with a potent lipogenic capacity. Thyroid hormones (TH) are essential for metabolism regulation and are associated with changes in body weight, energy expenditure, insulin sensitivity, and dyslipidemia. This study aimed to investigate the influence of fructose intake on thyroid function and thyroid-related genes. Male Wistar rats were divided into Control (CT, n=8) and Fructose (FT - 10% in drinking water, n=8) groups for three weeks. The FT group showed higher glycemia and serum triacylglycerol, indicating metabolic disturbances, and increased thyroid mass, accompanied by higher expression of Srebf1c and Lpl, suggesting increased lipid synthesis. The FT group also presented higher expression of Tpo and Dio1 in the thyroid, suggesting activation of the thyroid gland, but with no alterations in serum TH concentrations. Brown adipose tissue (BAT) of the FT group exhibited higher expression of Dio2, Thra, and Thrb, indicating increased T3 intra-tissue bioavailability and signaling. These responses were accompanied by increased BAT mass and higher expression of Adrb3, Pparg, Srebf1c, Fasn, Ppara, and Ucp1, suggesting increased BAT adrenergic sensitivity, lipid synthesis, oxidation, and thermogenesis. Therefore, short-term fructose consumption induced thyroid molecular alterations and increased BAT expression of thyroid hormone-related signaling genes that potentially contributed to higher BAT activity.
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Hypothyroidism is an endocrine disorder whose management raises many challenges in clinical practice. Its standard treatment is levothyroxine (LT4). The goal of the treatment is to normalize signs and symptoms, as well as to achieve thyroid-stimulating hormone (TSH) concentrations within the reference range, on an individual basis. It is known that 5-10% of hypothyroid patients remain symptomatic, despite achieving the target TSH levels, which, in turn, affects their quality of life. After ruling out other causes of non-thyroid origin for this persistence, it is suggested that these patients could benefit from the use of liothyronine (LT3), added to LT4, especially if polymorphism of the deiodinase 2 (D2) genes is documented. There exist a variety of LT3 preparations, whose concentrations vary from 5 to 50 ug, with the recommended LT4/LT3 ratio of 13:1-20:1. The goals of combination therapy should be to achieve a physiological ratio of free triiodothyronine/free thyroxine (FT3/FT4) and non-suppression of TSH. Because there is currently no guide that makes evidence-based recommendations on the use of LT3 in primary hypothyroidism, more clinical studies are needed to be able to identify hypothyroid patients who may benefit from the use of LT3, by identifying new biomarkers.
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Hipotiroidismo/tratamiento farmacológico , Tiroxina/uso terapéutico , Triyodotironina/uso terapéutico , Humanos , Yoduro Peroxidasa/uso terapéutico , Calidad de Vida , Hormonas Tiroideas , TirotropinaRESUMEN
RESUMEN Introducción: El correcto funcionamiento del eje hipotálamo-hipófisis-tiroides es indispensable para el crecimiento y desarrollo embrionario-fetal, al intervenir en la diferenciación de los tejidos, el desarrollo cerebral y somático, la maduración ósea y la regulación del metabolismo. El paso de las hormonas tiroideas maternas al feto a través de la placenta depende de transportadores transmembrana, enzimas desyodinasas (DIO2 y DIO3) y proteínas transportadoras (TTR). Objetivo: Identificar las zonas de expresión de DIO3 y TTR en la placenta de ratón Mus musculus E10.5, E12.5, E14.5. Métodos: La estructura placentaria y expresión de DIO3 y TTR fueron evaluadas con técnicas histoquímicas e inmunofluorescencia. Resultados: Desde E10.5 se encontraron las tres zonas placentarias, laberinto, zona de unión y decidua. En E12.5 se observó la conformación placentaria definitiva. DIO3 y TTR fueron detectadas en los tres estadios, con predominio en la zona del laberinto. Conclusión: DIO3 y TTR se expresan a lo largo del establecimiento y maduración de la placenta de ratón. El biomodelo murino es una herramienta útil para el estudio del transporte placentario de hormonas tiroideas desde la circulación materna a la fetal.
ABSTRACT Introduction: Correct functioning of hypothalamic-pituitary-thyroid axis is essential for embryonic-fetal growth and development, as it is involved in tissue differentiation, brain and somatic development, bone maturation and metabolic regulation. Maternal thyroid hormones passage to the fetus through the placenta depends on transmembrane transporters, deiodinase enzymes (DIO2 and DIO3) and carrier proteins (TTR). Objective: Identify DIO3 and TTR expression within placental layers of Mus musculus E10.5, E12.5 and E14.5. Methods: Placental structure, DIO3 and TTR expression were evaluated using histochemistry and immunofluorescence techniques. Results: We found that the three placental layers, labyrinth zone, junctional zone, and decidua were present since E10.5. At E12.5 placental final conformation was observed. DIO3 and TTR were detected in the three stages with a predominance in the labyrinth. Conclusion: DIO3 and TTR are expressed throughout the establishment and maturation of mouse placenta. Mice are a useful tool for studying how thyroid hormones are transported from maternal t° fetal circulation at the placenta.
RESUMO Introdução: O correto funcionamento do eixo hipotálamo-hipófise-tireoide é essencial para o crescimento e desenvolvimento embrionário-fetal, pois intervém na diferenciação dos tecidos, desenvolvimento cerebral e somático, maturação óssea e regulaçãodo metabolismo. A passagem dos hormônios tireoidianos maternos para o feto através da placenta depende de transportadores transmembranas, enzimas deiodinase (DIO2 e DIO3) e proteínas transportadoras (TTR). Objetivo: Identificar as zonas de expressão de DIO3 e TTR na placenta de rato Mus musculus E10.5, E12.5, E14.5. Métodos: A estrutura placentária e a expressão de DIO3 e TTR foram avaliadas com técnicas histoquímicas e imunofluorescência. Resultados: De E10.5 as três zonas placentárias, labirinto, zona de união e decídua foram encontradas. Em E12.5 a conformação definitiva da placenta foi observada. O DIO3 e o TTR foram detectados nas três fases, com predomínio na área do labirinto. Conclusão: DIO3 e TTR são expressos ao longo do estabelecimento e maturação da placenta de rato O biomodelo murino é uma ferramenta útil para o estudo do transporte placentário dos hormônios tireoidianos da circulação materna para a fetal.
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Aims: Liraglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist used as an anti-hyperglycemic agent in type 2 diabetes treatment and recently approved for obesity management. Weight loss is attributed to appetite suppression, but therapy may also increase energy expenditure. To further investigate the effect of GLP-1 signaling in thermogenic fat, we assessed adipose tissue oxygen consumption and type 2 deiodinase (D2) activity in mice treated with liraglutide, both basally and after ß3-adrenergic treatment. Methods: Male C57BL/6J mice were randomly assigned to receive liraglutide (400 µg/kg, n=12) or vehicle (n=12). After 16 days, mice in each group were co-treated with the selective ß3-adrenergic agonist CL316,243 (1 mg/kg, n=6) or vehicle (n=6) for 5 days. Adipose tissue depots were assessed for gene and protein expression, oxygen consumption, and D2 activity. Results: Liraglutide increased interscapular brown adipose tissue (iBAT) oxygen consumption and enhanced ß3-adrenergic-induced oxygen consumption in iBAT and inguinal white adipose tissue (ingWAT). These effects were accompanied by upregulation of UCP-1 protein levels in iBAT and ingWAT. Notably, liraglutide increased D2 activity without significantly upregulating its mRNA levels in iBAT and exhibited additive effects to ß3-adrenergic stimulation in inducing D2 activity in ingWAT. Conclusions: Liraglutide exhibits additive effects to those of ß3-adrenergic stimulation in thermogenic fat and increases D2 activity in BAT, implying that it may activate this adipose tissue depot by increasing intracellular thyroid activation, adding to the currently known mechanisms of GLP-1A-induced weight loss.
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Tejido Adiposo/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Yoduro Peroxidasa/metabolismo , Liraglutida/farmacología , Termogénesis/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Dioxoles/farmacología , Activación Enzimática , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Consumo de Oxígeno/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteína Desacopladora 1/metabolismo , Yodotironina Deyodinasa Tipo IIRESUMEN
Epidemiological and animal studies have demonstrated a strong association between selenium (Se) supplementation and metabolic disorders, we aimed to evaluate whether maternal Se supplementation was able to change metabolic parameters in rats' offspring. Moreover, as Se is a deiodinase (DIO) cofactor, we decided to investigate how thyroid hormones (THs) would be involved in such metabolic changes. Thereby, two groups (n = 6, ~250 g) of female Wistar rats underwent isotonic saline or sodium selenite (1 mg/kg, p.o.) treatments. Although there were no significant differences in body weight between groups, the Se treatment during pregnancy and lactation increased milk intake and the visceral white adipose tissue (WAT) in offspring. The rats whose mothers were treated with Se also presented an improvement in the glucose tolerance test and in the glucose-stimulated insulin secretion. Regarding the lipid metabolism, the Se group had a reduction of triglycerides in the liver and in WAT. These metabolic changes were accompanied by an increase in serum triiodothyronine (T3 ) and in DIO 2 expression in brown adipose tissue (BAT). We further demonstrate an increased expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) and nuclear respiratory factor-1 (NRF-1) mRNA in the liver. In adulthood offspring, Se supplementation programs thyroid function, glucose homeostasis, and feeding behaviour. Taken together, there is no indication that Se programming causes insulin resistance. Moreover, we conjecture that these metabolic responses are induced by increased thyroxine (T4 ) to T3 conversion by DIO2 in BAT and mediated by altered transcription factors expression associated with oxidative metabolism control in the liver.
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Suplementos Dietéticos/análisis , Lactancia/efectos de los fármacos , Metabolismo/efectos de los fármacos , Selenio/farmacología , Animales , Femenino , Masculino , Embarazo , Ratas , Ratas WistarRESUMEN
Some endocrine-disrupting chemicals (EDCs) can affect the endocrine system through covalent interactions with specific sites, leading to deregulation of physiological homeostasis. The acrylamide (AA) present in some fried or baked foods is an example of an electrophile molecule that is able to form adducts with nucleophilic regions of nervous system proteins leading to neurological defects. A positive correlation between increased urinary AA metabolite concentration and reduced levels of thyroid hormones (TH) was described in adolescents and young adults. Thus, this study aimed to evaluate whether AA affects the physiology of the hypothalamus-pituitary-thyroid (HPT) axis and the possible repercussions in peripheral TH-target systems. For this, male Wistar rats were exposed to doses of 2.5 or 5.0 mg AA/Kg/day, based on the LOAEL (Lowest Observed Adverse Effect Level) during prepubertal development. The expression of molecular markers of HPT functionality was investigated in the hypothalamus, pituitary, thyroid, heart and liver, as well as the hormonal and lipid profiles in blood samples. Herein, we showed that AA acts as EDCs for thyroid gland function, increasing the transcript expression of several proteins related to TH synthesis and altering hypothalamus-pituitary-thyroid axis homeostasis, an effect evidenced by the higher levels of THs in the serum. Compensatory mechanisms were observed in TH-target tissues, such as an increase in Dio3 mRNA expression in the liver and a reduction in Mct8 transcript content in the hearts of AA-treated rats. Together, these results pointed out an allostatic regulation of the HPT axis induced by AA and suggest that chronic exposure to it, mainly associated with food consumption, might be related to the higher prevalence of thyroid dysfunctions.
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MeCP2 is an X-linked gene; its mutation causes Rett Syndrome (RTT), a severe neurodevelopmental disability that affects mainly girls. Acting as a transcription factor, the MeCP2 protein is able to regulate several hormone-related genes, such as the thyroid hormones (TH), which are known to play an important role in the development of the central nervous system (CNS). Although only a few studies have associated RTT and TH, TH deficit can lead to neurological deregulation by triggering functional deficiencies during adulthood. Here, we used human-induced pluripotent stem cell (iPSC) to generate MeCP2-knockout neuronal progenitor cells and adult neurons. Using this cellular model, we then investigated the expression of genes associated with TH homeostasis, such as the TH transporters (LAT1, LAT2, MCT8, MCT10, and OATP4A1) and deiodinases (DIO1, 2, and 3). Then, we treated the neural cells with THs and analyzed the expression of several genes related to neurodevelopment and functional maintenance. Our results showed that several TH-related genes, such as deiodinases, are altered in RTT samples when compared to WT cells. Moreover, the treatment of the neural cells with THs increased the amount of MAP2 and synapsin-1 expression in RTT cells. Our work provided evidences that TH homeostasis is compromised in RTT-derived neural cells, which could be an important factor to contribute to the imbalance in the neurodevelopmental phenotype presented in this syndrome and can lead us to better understand other neurodevelopmental diseases.
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Regulación de la Expresión Génica , Células Madre Pluripotentes Inducidas/metabolismo , Yoduro Peroxidasa/genética , Proteínas de Transporte de Membrana/genética , Proteína 2 de Unión a Metil-CpG/deficiencia , Neuronas/metabolismo , Hormonas Tiroideas/metabolismo , Humanos , Yoduro Peroxidasa/metabolismo , Cariotipificación , Masculino , Proteínas de Transporte de Membrana/metabolismo , Redes y Vías Metabólicas , Modelos Biológicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Síndrome de Rett/enzimología , Síndrome de Rett/genéticaRESUMEN
Considering the recognized role of thyroid hormones on the cardiovascular system during health and disease, we hypothesized that type 2 deiodinase (D2) activity, the main activation pathway of thyroxine (T4)-to-triiodothyronine (T3), could be an important site to modulate thyroid hormone status, which would then constitute a possible target for β-adrenergic blocking agents in a myocardial infarction (MI) model induced by left coronary occlusion in rats. Despite a sustained and dramatic fall in serum T4 concentrations (60-70%), the serum T3 concentration fell only transiently in the first week post-infarction (53%) and returned to control levels at 8 and 12 weeks after surgery compared to the Sham group (P<0.05). Brown adipose tissue (BAT) D2 activity (fmol T4·min-1·mg ptn-1) was significantly increased by approximately 77% in the 8th week and approximately 100% in the 12th week in the MI group compared to that of the Sham group (P<0.05). Beta-blocker treatment (0.5 g/L propranolol given in the drinking water) maintained a low T3 state in MI animals, dampening both BAT D2 activity (44% reduction) and serum T3 (66% reduction in serum T3) compared to that of the non-treated MI group 12 weeks after surgery (P<0.05). Propranolol improved cardiac function (assessed by echocardiogram) in the MI group compared to the non-treated MI group by 40 and 57%, 1 and 12 weeks after treatment, respectively (P<0.05). Our data suggested that the beta-adrenergic pathway may contribute to BAT D2 hyperactivity and T3 normalization after MI in rats. Propranolol treatment maintained low T3 state and improved cardiac function additionally.
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Animales , Masculino , Ratas , Propranolol/administración & dosificación , Tiroxina/sangre , Tejido Adiposo Pardo/metabolismo , Agonistas Adrenérgicos beta/administración & dosificación , Yoduro Peroxidasa/metabolismo , Infarto del Miocardio/metabolismo , Tiroxina/efectos de los fármacos , Triyodotironina/efectos de los fármacos , Triyodotironina/sangre , Tejido Adiposo Pardo/efectos de los fármacos , Ratas Wistar , Modelos Animales de Enfermedad , Yoduro Peroxidasa/efectos de los fármacosRESUMEN
Thyroxine (T4) and 3,5,3'-triiodothyronine (T3) are secreted by the thyroid gland, while T3 is also generated from the peripheral metabolism of T4 by iodothyronine deiodinases types I and II. Several conditions like stress, diseases, and physical exercise can promote changes in local TH metabolism, leading to different target tissue effects that depend on the presence of tissue-specific enzymatic activities. The newly discovered physiological and pharmacological actions of T4 and T3 metabolites, such as 3,5-diiodothyronine (3,5-T2), and 3-iodothyronamine (T1AM) are of great interest. A classical thyroid hormone effect is the ability of T3 to increase oxygen consumption in almost all cell types studied. Approximately 30 years ago, a seminal report has shown that 3,5-T2 increased oxygen consumption more rapidly than T3 in hepatocytes. Other studies demonstrated that exogenous 3,5-T2 administration was able to increase whole body energy expenditure in rodents and humans. In fact, 3,5-T2 treatment prevents diabetic nephropathy, hepatic steatosis induced by high fat diet, insulin resistance, and weight gain during aging in Wistar male rats. The regulation of mitochondria is likely one of the most important actions of T3 and its metabolite 3,5-T2, which was able to restore the thermogenic program of brown adipose tissue (BAT) in hypothyroid rats, just as T3 does, while T1AM administration induced rapid hypothermia. T3 increases heart rate and cardiac contractility, which are hallmark effects of hyperthyroidism involved in cardiac arrhythmia. These deleterious cardiac effects were not observed with the use of 3,5-T2 pharmacological doses, and in contrast T1AM was shown to promote a negative inotropic and chronotropic action at micromolar concentrations in isolated hearts. Furthermore, T1AM has a cardioprotective effect in a model of ischemic/reperfusion injury in isolated hearts, such as occurs with T3 administration. Despite the encouraging possible therapeutic use of TH metabolites, further studies are needed to better understand their peripheral effects, when compared to T3 itself, in order to establish their risk and benefit. On this basis, the main peripheral effects of thyroid hormones and their metabolites in tissues, such as heart, liver, skeletal muscle, and BAT are discussed herein.
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Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an â¼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an "Alb-D2KO-like" metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia.
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Proteínas de Unión al ADN/genética , Hígado Graso/genética , Proteína Forkhead Box O1/genética , Hipercolesterolemia/genética , Animales , Proteínas de Unión al ADN/metabolismo , Hígado Graso/patología , Proteína Forkhead Box O1/metabolismo , RatonesRESUMEN
OBJECTIVES: To provide a comprehensive description of consumptive hypothyroidism syndrome (CHS), a severe form of hypothyroidism that occurs due to the high expression levels of thyroid hormone inactivation enzyme type 3 deiodinase (D3) in tumors. STUDY DESIGN: Case report and systematic review. RESULTS: A 7-month-old girl with a diagnosis of massive hepatic hemangioendotheliomas was treated with high doses of thyroid hormones and tumor-directed chemotherapy with vincristine. The tumor displayed excellent response, and euthyroid status was regained. A systematic review on the databases PubMed/Medline and Embase was performed, using the term "Consumptive AND "Hypothyroidism." From the 33 selected references, we extracted 42 case reports of CHS: 36 children and 6 adults. The laboratory profile at diagnosis displayed high TSH and low T4 and T3 serum levels. The serum reverse T3 and D3 activity levels were high in all patients tested. In children, 97% had vascular tumors, whereas in adults 33% were vascular tumors, 33% fibrous tumors, and 33% gastrointestinal stromal tumors. The conservative treatment was predominant in children, while in adults all cases were treated with surgery. Death occurred in 16% of children and 33% of adults. CONCLUSIONS: CHS is a rare form of hypothyroidism that occurs in children and adults, usually linked to hepatic vascular tumors. The condition is associated with high lethality. Prompt diagnosis, followed by high-dose thyroid hormone replacement and tumor-directed therapy are the keys to optimize outcomes.
RESUMEN
Early overnutrition (EO) during lactation leads to obesity, leptin resistance and lower thyroid hormone (TH) levels during adulthood. To better understand the biological significance of this thyroid hypofunction, we studied the long-term effects of postnatal EO on both the function of hypothalamic-pituitary-thyroid (HPT) axis and the metabolism and action of TH. To induce EO, the litter size was reduced to three pups per litter (small litter (SL) group) on the third day of lactation. In the controls (normal litter group), litter size was adjusted to 10 pups per litter. Rats were killed at PN180. TRH content and in vitro TSH were evaluated. Iodothyronine deiodinase (D1 and D2) activities were measured in different tissues. Mitochondrial α-glycerol-3-phosphate dehydrogenase (mGPD), uncoupling protein 1 (UCP1) and TH receptor (TRß1) were evaluated to assess TH action. The SL group presented lower TRH, intra-pituitary and released TSH levels, despite unchanged plasma TSH. They presented lower D1 activity in thyroid, muscle and white adipose tissue (WAT) and higher D2 activity in the hypothalamus, pituitary, brown adipose tissue (BAT) and WAT, which confirmed the hypothyroidism. UCP1 in BAT and TRß1 in WAT were decreased, which can contribute to a lower catabolic status. Despite the lower TH, the D2 activity in the thyroid, heart and testes was unchanged. Hepatic D1, mGPD and TRß1 were also unchanged in SL rats, suggesting that the TH conversion and action were preserved in the liver, even with lower TH. Thus, this model indicates that postnatal EO changes thyroid function in adult life in a tissue-specific way, which can help in the understanding of obesogenesis.
Asunto(s)
Hipotiroidismo/metabolismo , Lactancia/metabolismo , Obesidad/metabolismo , Hipernutrición/metabolismo , Glándula Tiroides/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Femenino , Glicerolfosfato Deshidrogenasa/metabolismo , Hipotálamo/metabolismo , Hipotiroidismo/etiología , Yoduro Peroxidasa/metabolismo , Masculino , Obesidad/etiología , Hipernutrición/complicaciones , Hipófisis/metabolismo , Ratas , Ratas WistarRESUMEN
Postnatal nicotine exposure leads to obesity and hypothyroidism in adulthood. We studied the effects of maternal nicotine exposure during lactation on thyroid hormone (TH) metabolism and function in adult offspring. Lactating rats received implants of osmotic minipumps releasing nicotine (NIC, 6âmg/kg per day s.c.) or saline (control) from postnatal days 2 to 16. Offspring were killed at 180 days. We measured types 1 and 2 deiodinase activity and mRNA, mitochondrial α-glycerol-3-phosphate dehydrogenase (mGPD) activity, TH receptor (TR), uncoupling protein 1 (UCP1), hypothalamic TRH, pituitary TSH, and in vitro TRH-stimulated TSH secretion. Expression of deiodinase mRNAs followed the same profile as that of the enzymatic activity. NIC exposure caused lower 5'-D1 and mGPD activities; lower TRß1 content in liver as well as lower 5'-D1 activity in muscle; and higher 5'-D2 activity in brown adipose tissue (BAT), heart, and testis, which are in accordance with hypothyroidism. Although deiodinase activities were not changed in the hypothalamus, pituitary, and thyroid of NIC offspring, UCP1 expression was lower in BAT. Levels of both TRH and TSH were lower in offspring exposed to NIC, which presented higher basal in vitro TSH secretion, which was not increased in response to TRH. Thus, the hypothyroidism in NIC offspring at adulthood was caused, in part, by in vivo TRH-TSH suppression and lower sensitivity to TRH. Despite the hypothyroid status of peripheral tissues, these animals seem to develop an adaptive mechanism to preserve thyroxine to triiodothyronine conversion in central tissues.