RESUMO
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.
Assuntos
Iodeto Peroxidase , Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Masculino , Iodeto Peroxidase/metabolismo , Ratos Sprague-Dawley , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismoRESUMO
The thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), are of vital importance for fetal development. The concentration of THs in fetal circulation varies throughout gestation and differs from the concentration in the maternal serum, indicating the presence of maternal-fetal thyroid homeostasis regulatory mechanisms in the placenta. The passage of THs from maternal circulation to fetal circulation is modulated by plasma membrane transporters, enzymes, and carrier proteins. Monocarboxylate transporter 8, iodothyronine deiodinases (DIO2 and DIO3), and transthyretin are especially involved in this maternal-fetal thyroid modulation, shown by a greater expression in the placenta. THs also play a role in placental development and as expected, abnormal variations in TH levels are associated with pregnancy complications and can result in damage to the fetus. Although new evidence regarding TH regulation during pregnancy and its effects in the mother, placenta, and fetus has been published, many aspects of these interactions are still poorly understood. The objective of this review is to provide an evidence-based update, drawn from current data, on the metabolism and transport of THs in the placenta and their vital role in the maternal-fetal relationship.
Assuntos
Placenta , Hormônios Tireóideos , Feminino , Gravidez , Humanos , Placenta/metabolismo , Hormônios Tireóideos/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Iodeto Peroxidase/metabolismoRESUMO
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.
Assuntos
Tecido Adiposo/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Iodeto Peroxidase/metabolismo , Liraglutida/farmacologia , Termogênese/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Dioxóis/farmacologia , Ativação Enzimática , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteína Desacopladora 1/metabolismo , Iodotironina Desiodinase Tipo IIRESUMO
PURPOSE: The potential benefits of treating subclinical hypothyroidism (SCH) are unclear and still controversial. Thus, we surgically induced SCH in rats and evaluated the effects of thyroxine (T4) replacement on the gene expression levels of deiodinases and thyroid hormone (TH) transporters in different tissues. METHODS: SCH was induced by hemithyroid electrocauterization. The control animals underwent the same surgical procedure but were not subjected to electrocauterization (sham). After 14 days, half of the SCH animals were treated with T4 (SCH + T4). At the end of the experimental protocol, all of the rats were euthanized, serum hormone concentrations were measured, and RNA analyses were performed on different tissues and organs. RESULTS: Consistent with previous studies, we observed increased TSH levels, normal TH levels, and reduced hypothalamic TRH expression in the SCH group. Additionally, Dio2 mRNA expression was downregulated in the hippocampus and pituitary, and Dio1 was upregulated in the kidney and pituitary of the SCH animals. The changes in Dio3 expression were tissue-specific. Concerning TH transporters, Mct10 expression was upregulated in the pituitary, kidney, hypothalamus, and hippocampus, and Mct8 expression was downregulated in the kidney of the SCH group. Crym expression was upregulated in the kidney and pituitary. Notably, T4 replacement significantly attenuated serum TSH levels and reverted Dio1, Dio2, Mct10, and Crym expression in the pituitary, hippocampus, and kidney to levels that were similar to the sham group. Tissue-specific responses were also observed in the liver and hypothalamus. CONCLUSION: Our results indicate that treatment of SCH should be considered before the appearance of clinical symptoms of hypothyroidism.
Assuntos
Hipotireoidismo/tratamento farmacológico , Iodeto Peroxidase/metabolismo , Proteínas de Ligação a Tiroxina/metabolismo , Tiroxina/uso terapêutico , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/fisiologia , Hipotireoidismo/etiologia , Iodeto Peroxidase/genética , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Proteínas de Ligação a Tiroxina/genética , Cristalinas muRESUMO
Thyroid hormones (THs) are critical regulators of cellular processes, while changes in their levels impact all the hallmarks of cancer. Disturbed expression of type 3 deiodinase (DIO3), the main TH-inactivating enzyme, occurs in several human neoplasms and has been associated with adverse outcomes. Here, we investigated the patterns of DIO3 expression and its prognostic significance in breast cancer. DIO3 expression was evaluated by immunohistochemistry in a primary cohort of patients with breast cancer and validated in a second cohort using RNA sequencing data from the TCGA database. DNA methylation data were obtained from the same database. DIO3 expression was present in normal and tumoral breast tissue. Low levels of DIO3 expression were associated with increased mortality in the primary cohort. Accordingly, low DIO3 mRNA levels were associated with an increased risk of death in a multivariate model in the validation cohort. DNA methylation analysis revealed that the DIO3 gene promoter is hypermethylated in tumors when compared to normal tissue. In conclusion, DIO3 is expressed in normal and tumoral breast tissue, while decreased expression relates to poor overall survival in breast cancer patients. Finally, loss of DIO3 expression is associated with hypermethylation of the gene promoter and might have therapeutic implications.
Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/epidemiologia , Iodeto Peroxidase/metabolismo , Hormônios Tireóideos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Estudos de Coortes , Metilação de DNA/genética , Feminino , Fibroadenoma/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Iodeto Peroxidase/genética , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Taxa de SobrevidaRESUMO
Background: Sepsis can cause the nonthyroidal illness syndrome (NTIS), resulting in perturbed thyroid hormone (TH) signaling and reduced thyroxine (T4) levels. TH is a major regulator of muscle function, via its influence on mitochondria. This study aimed at evaluating the relationship between TH signaling, mitochondrial function, and the antioxidant defense system in the diaphragms of septic mice. Methods: Male C57Bl/6 mice were divided into two groups: cecal ligation and puncture (CLP) and sham. Twenty-four hours after surgery, plasma, diaphragms, and livers were collected. TH metabolism and responses were analyzed by measuring messenger RNA (mRNA) expression of Dio1 in the liver, and Thra, Thrb, Dio2, Slc16a10, and Slc16a2 (encodes MCT 10 and 8), in the diaphragm. T4 plasma levels were measured by radioimmunoassay. Damage to diaphragm mitochondria was assessed by electron microscopy and real-time polymerase chain reaction (qPCR), and function with oxygraphy. The diaphragm antioxidative defense system was examined by qPCR, analyzing superoxide dismutase (SOD) 1 (Sod1), mitochondrial superoxide dismutase (SOD 2; Sod2), extracellular superoxide dismutase (SOD 3; Sod3), glutathione peroxidase 1 (Gpx1), and catalase (Cat) expression. The effect of TH replacement was tested by treating the mice with T4 and triiodothyronine (T3) (CLP+TH) after surgery. Results: CLP mice presented reduced total plasma T4 concentrations, downregulated Dio1, and upregulated Il1b mRNA expression in the liver. CLP mice also displayed downregulated Thra, Thrb, Slc16a10, and Slc16a2 expression in the diaphragm, suggesting that TH signaling was compromised. The expression of Ppargc1a (encoding PGC1a) was downregulated, which correlated with the decrease in the number of total mitochondria, increase in the percentage of injured mitochondria, downregulation of respiratory chain complex 2 and 3 mRNA expression, and reduced maximal respiration. In addition, septic animals presented a three-fold increase in Ucp3 and G6pdh expression; downregulated Sod3, Gpx1, and Cat expression; and upregulated Sod2 expression, potentially due to elevated reactive oxygen species levels. The mitochondrial number and the percentage of injured mitochondrial were similar between sham and CLP+TH mice. Conclusions: Sepsis induced responses consistent with NTIS, resulted in mitochondrial damage and functional impairment, and modulated the expression of key antioxidant enzymes in the diaphragm. Thus, impaired diaphragm function during sepsis seems to involve altered local TH signaling, mitochondrial dysfunction, and oxidative stress defense.
Assuntos
Diafragma/metabolismo , Mitocôndrias/metabolismo , Sepse/metabolismo , Transdução de Sinais/fisiologia , Hormônios Tireóideos/metabolismo , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Fígado/metabolismo , Camundongos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
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 ß-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.
Assuntos
Tecido Adiposo Marrom/metabolismo , Antagonistas Adrenérgicos beta/administração & dosagem , Iodeto Peroxidase/metabolismo , Infarto do Miocárdio/metabolismo , Propranolol/administração & dosagem , Tiroxina/sangue , Tri-Iodotironina/sangue , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Iodeto Peroxidase/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Tiroxina/efeitos dos fármacos , Tri-Iodotironina/efeitos dos fármacos , Iodotironina Desiodinase Tipo IIRESUMO
AIMS: We assessed the effects of a short-term exercise training on cardiac function, oxidative stress markers, and type 3 iodothyronine deiodinase (D3) activity in cardiac tissue of spontaneously hypertensive rats (SHR) following experimental myocardial infarction (MI). METHODS: Twenty-four SHR (aged 3 months) were allocated to 4 groups: sham+sedentary, sham+trained, MI+sedentary and MI+trained. MI was performed by permanent ligation of the coronary artery. Exercise training (treadmill) started 96 hours after MI and lasted for 4 weeks (~60% maximum effort, 4x/week and 40 min/day). Cardiac function (echocardiography), thioredoxin reductase (TRx), total carbonyl levels, among other oxidative stress markers and D3 activity were measured. A Generalized Estimating Equation was used, followed by Bonferroni's test (p<0.05). RESULTS: MI resulted in an increase in left ventricular mass (p = 0.002) with decreased cardiac output (~22.0%, p = 0.047) and decreased ejection fraction (~41%, p = 0.008) as well as an increase in the carbonyl levels (p = 0.001) and D3 activity (~33%, p<0.001). Exercise training resulted in a decrease in left ventricular mass, restored cardiac output (~34%, p = 0.048) and ejection fraction (~20%, p = 0.040), increased TRx (~85%, p = 0.007) and reduced carbonyl levels (p<0.001) and D3 activity (p<0.001). CONCLUSIONS: Our short-term exercise training helped reverse the effects of MI on cardiac function. These benefits seem to derive from a more efficient antioxidant response and lower D3 activity in cardiac tissue.
Assuntos
Coração/fisiopatologia , Condicionamento Físico Animal/fisiologia , Função Ventricular Esquerda/fisiologia , Animais , Antioxidantes/farmacologia , Pressão Sanguínea , Vasos Coronários/fisiopatologia , Ecocardiografia , Testes de Função Cardíaca/métodos , Iodeto Peroxidase/metabolismo , Masculino , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/métodos , Ratos , Ratos Endogâmicos SHRRESUMO
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.
Assuntos
Regulação da Expressão Gênica , Células-Tronco Pluripotentes Induzidas/metabolismo , Iodeto Peroxidase/genética , Proteínas de Membrana Transportadoras/genética , Proteína 2 de Ligação a Metil-CpG/deficiência , Neurônios/metabolismo , Hormônios Tireóideos/metabolismo , Humanos , Iodeto Peroxidase/metabolismo , Cariotipagem , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Redes e Vias Metabólicas , Modelos Biológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Síndrome de Rett/enzimologia , Síndrome de Rett/genéticaRESUMO
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.