RESUMEN
The conversion of white adipose cells into beige adipose cells is known as browning, a process affecting energy metabolism. It has been shown that 3,5 diiodo-l-thyronine (T2), an endogenous metabolite of thyroid hormones, stimulates energy expenditure and a reduction in fat mass. In light of the above, the purpose of this study was to test whether in an animal model of fat accumulation, T2 has the potential to activate a browning process and to explore the underlying mechanism. Three groups of rats were used: (i) receiving a standard diet for 14 weeks; (ii) receiving a high-fat diet (HFD) for 14 weeks; and (iii) receiving a high fat diet for 10 weeks and being subsequently treated for four weeks with an HFD together with the administration of T2. We showed that T2 was able to induce a browning in the white adipose tissue of T2-treated rats. We also showed that some miRNA (miR133a and miR196a) and MAP kinase 6 were involved in this process. These results indicate that, among others, the browning may be another cellular/molecular mechanism by which T2 exerts its beneficial effects of contrast to overweight and of reduction of fat mass in rats subjected to HFD.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Dieta Alta en Grasa , Diyodotironinas/farmacología , Vivienda para Animales , Sobrepeso/patología , Temperatura , Adenilato Quinasa/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Adiposidad/efectos de los fármacos , Animales , Diyodotironinas/administración & dosificación , Regulación hacia Abajo/efectos de los fármacos , Fibronectinas/sangre , Insulina/metabolismo , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Fosforilación/efectos de los fármacos , Ratas Wistar , Factores de Transcripción/metabolismo , Proteína Desacopladora 1/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
Cell membrane thyroid hormone (TH) transport can be facilitated by the monocarboxylate transporter 8 (MCT8), encoded by the solute carrier family 16 member 2 (SLC16A2) gene. Human mutations of the gene, SLC16A2, result in the X-linked-inherited psychomotor retardation and hypomyelination disorder, Allan-Herndon-Dudley syndrome (AHDS). We posited that abrogating MCT8-dependent TH transport limits oligodendrogenesis and myelination. We show that human oligodendrocytes (OL), derived from the NKX2.1-GFP human embryonic stem cell (hESC) reporter line, express MCT8. Moreover, treatment of these cultures with DITPA (an MCT8-independent TH analog), up-regulates OL differentiation transcription factors and myelin gene expression. DITPA promotes hESC-derived OL myelination of retinal ganglion axons in co-culture. Pharmacological and genetic blockade of MCT8 induces significant OL apoptosis, impairing myelination. DITPA treatment limits OL apoptosis mediated by SLC16A2 down-regulation primarily signaling through AKT phosphorylation, driving myelination. Our results highlight the potential role of MCT8 in TH transport for human OL development and may implicate DITPA as a promising treatment for developmentally-regulated myelination in AHDS.
Asunto(s)
Diferenciación Celular/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonía Muscular/genética , Atrofia Muscular/genética , Neurogénesis/genética , Transporte Biológico/genética , Línea Celular , Diyodotironinas/administración & dosificación , Células Madre Embrionarias Humanas/efectos de los fármacos , Humanos , Discapacidad Intelectual Ligada al Cromosoma X/tratamiento farmacológico , Discapacidad Intelectual Ligada al Cromosoma X/patología , Hipotonía Muscular/tratamiento farmacológico , Hipotonía Muscular/patología , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/patología , Mutación , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Oligodendroglía/patología , Propionatos/administración & dosificación , Simportadores , Hormonas Tiroideas/genética , Hormonas Tiroideas/metabolismoRESUMEN
The role of 3,5-diiodo-L-thyronine (T2), initially considered only a 3,3',5-triiodo-L-thyronine (T3) catabolite, in the bioenergetic metabolism is of growing interest. In this study we investigated the acute effects (within 1 h) of T2 administration to hypothyroid rats on liver mitochondria fatty acid uptake and ß-oxidation rate, mitochondrial efficiency (by measuring proton leak) and mitochondrial oxidative damage (by determining H2O2 release). Fatty acid uptake into mitochondria was measured assaying carnitine palmitoyl transferase (CPT) I and II activities, and fatty acid ß-oxidation using palmitoyl-CoA as a respiratory substrate. Mitochondrial fatty acid pattern was defined by gas-liquid chromatography. In hypothyroid + T2 vs hypothyroid rats we observed a raise in the serum level of nonesterified fatty acids (NEFA), in the mitochondrial CPT system activity and in the fatty acid ß-oxidation rate. A parallel increase in the respiratory chain activity, mainly from succinate, occurs. When fatty acids are chelated by bovine serum albumin, a T2-induced increase in both state 3 and state 4 respiration is observed, while, when fatty acids are present, mitochondrial uncoupling occurs together with increased proton leak, responsible for mitochondrial thermogenesis. T2 administration decreases mitochondrial oxidative stress as determined by lower H2O2 production. We conclude that in rat liver mitochondria T2 acutely enhances the rate of fatty acid ß-oxidation, and the activity of the downstream respiratory chain. The T2-induced increase in proton leak may contribute to mitochondrial thermogenesis and to the reduction of oxidative stress. Our results strengthen the previously reported ability of T2 to reduce adiposity, dyslipidemia and to prevent liver steatosis.
Asunto(s)
Diyodotironinas/farmacología , Metabolismo Energético/efectos de los fármacos , Hipotiroidismo/tratamiento farmacológico , Mitocondrias Hepáticas/metabolismo , Animales , Diyodotironinas/administración & dosificación , Transporte de Electrón/efectos de los fármacos , Ácidos Grasos/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Desacopladores/farmacologíaRESUMEN
Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.
Asunto(s)
Diyodotironinas/farmacología , Proteínas de Transporte de Membrana/deficiencia , Discapacidad Intelectual Ligada al Cromosoma X/prevención & control , Hipotonía Muscular/prevención & control , Atrofia Muscular/prevención & control , Propionatos/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Diyodotironinas/administración & dosificación , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Glutatión Transferasa/genética , Glicerol-3-Fosfato Deshidrogenasa (NAD+)/genética , Humanos , Inyecciones Intraperitoneales , Isoenzimas/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Proteínas de Transporte de Membrana/genética , Discapacidad Intelectual Ligada al Cromosoma X/sangre , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Transportadores de Ácidos Monocarboxílicos , Hipotonía Muscular/sangre , Hipotonía Muscular/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/sangre , Atrofia Muscular/metabolismo , Propionatos/administración & dosificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Simportadores , Hormonas Tiroideas/sangre , Tirotropina/sangreRESUMEN
The use of neuroprotective strategies to mitigate the fatal consequences of ischemic brain stroke is a focus of robust research activity. We have previously demonstrated that thyroid hormone (T3; 3,3',5-triiodo-l-thyronine) possesses neuroprotective and anti-edema activity in pre-stroke treatment regimens when administered as a solution or as a nanoparticle formulation. In this study we have extended our evaluation of thyroid hormone use in animal models of brain stroke. We have used both transient middle cerebral artery occlusion (t-MCAO) and permanent (p-MCAO) models of ischemic brain stroke. A significant reduction of tissue infarction and a concurrent decrease in edema were observed in the t-MCAO model of brain stroke. However, no benefit of T3 was observed in p-MCAO stroke setting. Significant improvement of neurological outcomes was observed upon T3 treatment in t-MCAO mice. Further, we tested T2 (3,5-diiodo-l-thyronine) a natural deiodination metabolite of T3 in MCAO model of brain stroke. T2 potently decreased infarct size as well as edema formation. Additionally, we report here that T3 suppresses the expression of aquaporin-4 (AQP4) water channels which could be a likely mechanism of its anti-edema activity. Our studies provide evidence to stimulate clinical development of thyroid hormones for use in ischemic brain stroke.
Asunto(s)
Acuaporina 4/fisiología , Edema Encefálico/tratamiento farmacológico , Diyodotironinas/administración & dosificación , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Triyodotironina/administración & dosificación , Animales , Edema Encefálico/patología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Infarto de la Arteria Cerebral Media/patología , Inyecciones Intravenosas , Masculino , Ratones , Accidente Cerebrovascular/patologíaRESUMEN
In general, 3,5-diiodothyronine (3,5-T2) increases the resting metabolic rate and oxygen consumption, exerting short-term beneficial metabolic effects on rats subjected to a high-fat diet. Our aim was to evaluate the effects of chronic 3,5-T2 administration on the hypothalamus-pituitary-thyroid axis, body mass gain, adipose tissue mass, and body oxygen consumption in Wistar rats from 3 to 6 months of age. The rats were treated daily with 3,5-T2 (25, 50, or 75âµg/100âg body weight, s.c.) for 90 days between the ages of 3 and 6 months. The administration of 3,5-T2 suppressed thyroid function, reducing not only thyroid iodide uptake but also thyroperoxidase, NADPH oxidase 4 (NOX4), and thyroid type 1 iodothyronine deiodinase (D1 (DIO1)) activities and expression levels, whereas the expression of the TSH receptor and dual oxidase (DUOX) were increased. Serum TSH, 3,3',5-triiodothyronine, and thyroxine were reduced in a 3,5-T2 dose-dependent manner, whereas oxygen consumption increased in these animals, indicating the direct action of 3,5-T2 on this physiological variable. Type 2 deiodinase activity increased in both the hypothalamus and the pituitary, and D1 activities in the liver and kidney were also increased in groups treated with 3,5-T2. Moreover, after 3 months of 3,5-T2 administration, body mass and retroperitoneal fat pad mass were significantly reduced, whereas the heart rate and mass were unchanged. Thus, 3,5-T2 acts as a direct stimulator of energy expenditure and reduces body mass gain; however, TSH suppression may develop secondary to 3,5-T2 administration.
Asunto(s)
Diyodotironinas/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Hipotiroidismo/metabolismo , Glándula Tiroides/efectos de los fármacos , Animales , Metabolismo Basal/efectos de los fármacos , Diyodotironinas/administración & dosificación , Oxidasas Duales , Flavoproteínas/genética , Flavoproteínas/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Hipotiroidismo/sangre , Hipotiroidismo/genética , Immunoblotting , Yoduro Peroxidasa/metabolismo , Yoduros/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , NADPH Oxidasa 4 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Tirotropina/genética , Receptores de Tirotropina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Glándula Tiroides/metabolismo , Glándula Tiroides/fisiopatología , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangre , Yodotironina Deyodinasa Tipo IIRESUMEN
Recent studies in our laboratory have shown that in some teleosts, 3,5-di-iodothyronine (T2 or 3,5-T2) is as bioactive as 3,5,3'-tri-iodothyronine (T3) and that its effects are in part mediated by a TRß1 (THRB) isoform that contains a 9-amino acid insert in its ligand-binding domain (long TRß1 (L-TRß1)), whereas T3 binds preferentially to a short TRß1 (S-TRß1) isoform that lacks this insert. To further understand the functional relevance of T2 bioactivity and its mechanism of action, we used in vivo and ex vivo (organotypic liver cultures) approaches and analyzed whether T3 and T2 differentially regulate the S-TRß1 and L-TRß1s during a physiological demand such as growth. In vivo, T3 and T2 treatment induced body weight gain in tilapia. The expression of L-TRß1 and S-TRß1 was specifically regulated by T2 and T3 respectively both in vivo and ex vivo. The TR antagonist 1-850 effectively blocked thyroid hormone-dependent gene expression; however, T3 or T2 reversed 1-850 effects only on S-TRß1 or L-TRß1 expression, respectively. Together, our results support the notion that both T3 and T2 participate in the growth process; however, their effects are mediated by different, specific TRß1 isoforms.
Asunto(s)
Diyodotironinas/farmacología , Receptores beta de Hormona Tiroidea/metabolismo , Tilapia/crecimiento & desarrollo , Tilapia/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Diyodotironinas/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Isoformas de Proteínas , Receptores beta de Hormona Tiroidea/agonistas , Receptores beta de Hormona Tiroidea/antagonistas & inhibidores , Tilapia/genética , Triyodotironina/metabolismo , Yodotironina Deyodinasa Tipo IIRESUMEN
3,5-Diiodo-l-thyronine (T2) powerfully reduces adiposity in rats fed a high-fat diet (HFD), stimulating (in the liver) fatty acid oxidation and mitochondrial uncoupling, and strongly counteracting steatosis, a condition commonly associated with diet-induced obesity. Proteomics offer unique possibilities for the investigation of changes in the levels and modifications of proteins. Here, combining 2D-E, mass spectrometry, and blue native (BN) PAGE, we studied how the subcellular hepatic phenotype responds to HFD and T2-treatment. By identifying differentially expressed proteins and analyzing their interrelation [using the Ingenuity Pathway Analysis (IPA) platform], we obtained an integrated view of the phenotypic/metabolic adaptations occurring in the liver proteome during HFD with or without T2-treatment. Interestingly, T2 counteracted several HFD-induced changes, mostly in mitochondria. BN-PAGE and subsequent in-gel activity analysis of OXPHOS complexes revealed a modified profile of individual complexes in HFD mitochondria vs. normal ones. This pattern was re-normalized in mitochondria from T2-treated HFD animals. These data indicate that in HFD rats, the effects of T2 on the liver proteome cause it to resemble that associated with a non-steatotic condition. The identified metabolic pathways (mainly at the mitochondrial level) may be responsible for the beneficial effects of T2 on liver adiposity and metabolism.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Diyodotironinas/farmacología , Electroforesis en Gel Bidimensional/métodos , Hígado/metabolismo , Transducción de Señal/efectos de los fármacos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Animales , Biología Computacional , Citoplasma/metabolismo , Diyodotironinas/administración & dosificación , Conducta Alimentaria/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Proteínas Mitocondriales/química , Proteínas Mitocondriales/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Proteómica , Ratas , Ratas Wistar , Coloración y Etiquetado , Triglicéridos/metabolismoRESUMEN
BACKGROUND: In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. METHODS AND RESULTS: This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (-20%), low-density lipoprotein cholesterol (-30%), and body weight (-11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. CONCLUSIONS: DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.
Asunto(s)
Diyodotironinas/administración & dosificación , Diyodotironinas/efectos adversos , Insuficiencia Cardíaca/tratamiento farmacológico , Propionatos/administración & dosificación , Propionatos/efectos adversos , Adolescente , Adulto , Anciano , Peso Corporal , Colesterol/sangre , Método Doble Ciego , Fatiga/sangre , Fatiga/inducido químicamente , Femenino , Enfermedades Gastrointestinales/sangre , Enfermedades Gastrointestinales/inducido químicamente , Insuficiencia Cardíaca/sangre , Humanos , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Hormonas Tiroideas , Estados Unidos , United States Department of Veterans Affairs , Resistencia Vascular/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: Mitochondrial dysfunction is central to the physiopathology of steatosis and/or non-alcoholic fatty liver disease. In this study on rats we investigated whether 3,5-diiodo-l-thyronine (T2), a biologically active iodothyronine, acting at mitochondrial level is able to reverse hepatic steatosis after its induction through a high-fat diet. METHODS: Hepatic steatosis was induced by long-term high-fat feeding of rats for six weeks which were then fed the same high-fat diet for the next 4 weeks and were simultaneously treated or not treated with T2. Histological analyses were performed on liver sections (by staining with Sudan black B). In liver mitochondria fatty acid oxidation rate, mitochondrial efficiency (by measuring proton conductance) and mitochondrial oxidative stress (by measuring H(2)O(2) release, aconitase and SOD activity) were detected. RESULTS: Stained sections showed that T2 treatment reduced hepatic fatty accumulation induced by a high-fat diet. At the mitochondrial level, the fatty acid oxidation rate and carnitine palmitoyl transferase activity were enhanced by T2 treatment. Moreover, by stimulating mitochondrial uncoupling, T2 caused less efficient utilization of fatty acid substrates and ameliorated mitochondrial oxidative stress. CONCLUSION: These data demonstrate that T2, by activating mitochondrial processes, markedly reverses hepatic steatosis in vivo.
Asunto(s)
Diyodotironinas/uso terapéutico , Hígado Graso/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Alanina Transaminasa/sangre , Animales , Grasas de la Dieta/administración & dosificación , Diyodotironinas/administración & dosificación , Hígado Graso/metabolismo , Hígado Graso/patología , Lípidos/sangre , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Wistar , Tirotropina/sangre , Aumento de Peso/efectos de los fármacosRESUMEN
Patients with hypothyroidism are at a higher risk for coronary vascular disease. Patients with diabetes and related vascular complications also have an increased incidence of low thyroid function. While thyroid hormones (THs) may be key regulators of a healthy vasculature, potential undesirable side effects hinder their use in the treatment of vascular disorders. TH analogs such as 3,5-diiodothyropropionic acid (DITPA) may provide a safer treatment option. However, the relative potency of DITPA on vascular growth, cardiac function, and metabolism is poorly understood. We hypothesized that the vascular growth-promoting effects of DITPA can be obtained with a minimum effect on cardiac function. Thyroidectomized Sprague-Dawley rats were given slow-release pellets with either thyroxine (T4, 2.7 or 5.2 mg) or DITPA (80 mg) for 6 wk and were compared with placebo. Heart mass, body mass, body temperature, serum THs, cardiac function (echocardiograms and hemodynamics), and myocardial arteriolar density were determined. Hypothyroidism led to reductions in cardiac function, heart mass, body temperature, and myocardial arterioles. High-dose T4 prevented arteriolar loss and the development of hypothyroidism. Low-dose T4 partially prevented the reduction in cardiac function but had minimal effects on arteriolar loss. In contrast, DITPA treatment prevented myocardial arteriolar loss but not the progression of hypothyroid-induced changes in cardiac function. The results suggested that DITPA can promote a healthy vasculature independently from its thyroid-related metabolic effects. Drugs in this class may provide new therapeutic options for patients with vascular disease.
Asunto(s)
Inductores de la Angiogénesis/farmacología , Vasos Coronarios/efectos de los fármacos , Diyodotironinas/farmacología , Cardiopatías/tratamiento farmacológico , Hipotiroidismo/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Propionatos/farmacología , Tiroxina/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Inductores de la Angiogénesis/administración & dosificación , Animales , Temperatura Corporal/efectos de los fármacos , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/fisiopatología , Diyodotironinas/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Implantes de Medicamentos , Cardiopatías/diagnóstico por imagen , Cardiopatías/etiología , Cardiopatías/fisiopatología , Hemodinámica/efectos de los fármacos , Hipotiroidismo/complicaciones , Hipotiroidismo/diagnóstico por imagen , Hipotiroidismo/fisiopatología , Masculino , Propionatos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Tiroidectomía , Tiroxina/administración & dosificación , Tiroxina/sangre , Triyodotironina/sangre , UltrasonografíaRESUMEN
In rats fed a high fat diet (HFD), long-term administration of 3,5-diiodo-L-thyronine (T2), a naturally occurring iodothyronine, was shown to reduce body-weight gain, fat mass, and hepatic lipid accumulation. This work was aimed at investigating the mechanisms of T2 action in the liver of HFD rats. The results show that HFD induces liver lipid peroxidation and stimulates the activity of enzymes involved in hydrogen peroxide (H2O2) metabolism, catalase in particular. Moreover, quantitative RT-PCR revealed HFD-induced upregulation of the transcription factor PPAR alpha, as well as of metallothionein isoforms (MT-1 and MT-2). T2 administration prevented the HDF-induced lipid peroxidation, as well as the increase in H2O2 metabolism, and reduced the upregulation of both PPAR alpha and MT-2. These data demonstrate that in the liver of HFD rats, T2 prevents both lipid accumulation and oxidative stress associated with increased fat metabolism.
Asunto(s)
Grasas de la Dieta/farmacología , Diyodotironinas/administración & dosificación , Hígado/efectos de los fármacos , Alimentación Animal , Animales , Peso Corporal/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Lípidos/sangre , Hígado/citología , Hígado/metabolismo , Masculino , Metalotioneína/genética , Metalotioneína/metabolismo , Estrés Oxidativo/genética , PPAR alfa/genética , Ratas , Ratas Wistar , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genéticaRESUMEN
We investigated the mechanism by which 3,5-diiodo-l-thyronine (T2) affects skeletal muscle mitochondrial bioenergetic parameters following its acute administration to hypothyroid rats. One hour after injection, T2 increased both coupled and uncoupled respiration rates by +27% and +42%, respectively. Top-down elasticity analysis revealed that these effects were the result of increases in the substrate oxidation and mitochondrial uncoupling. Discriminating between proton-leak and redox-slip processes, we identified an increased mitochondrial proton conductance as the "pathway" underlying the effect of T2 on mitochondrial uncoupling. As a whole, these results may provide a mechanism by which T2 rapidly affects energy metabolism in hypothyroid rats.
Asunto(s)
Diyodotironinas/administración & dosificación , Diyodotironinas/farmacología , Metabolismo Energético/efectos de los fármacos , Hipotiroidismo/metabolismo , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Animales , Carbonil Cianuro p-Trifluorometoxifenil Hidrazona/farmacología , Respiración de la Célula/efectos de los fármacos , Cinética , Masculino , Malonatos/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Oligomicinas/farmacología , Oxidación-Reducción/efectos de los fármacos , Fosforilación/efectos de los fármacos , Protones , Ratas , Ratas WistarRESUMEN
As thyroid hormones are known to have long-term and short-term effects on metabolism and only the long term effects been examined in detail, in the present investigation a comparative study has been mad to elucidate the short-term effects of T3 and T2 on enzymes of lipid metabolism in a fish Anabas testudineus. The time dependent studies involved assays of specific, activities of lipogenic enzymes and membrane ATPase- Anabas responded to T3 treatment with a significant increase in the liver malic enzyme activity (after 1 hr) and the activity pattern was reversed after 6 hrs in low dose (0.25microg T3) treated group. T2 treatment also increased the malic enzyme activity within one hour after administration. T2 caused an Increase, in the activity of glucose-6-phosphate dehydrogenase under both time courses, HMG-CoA Reductase activity was reduced upon T3 and T2 administration except for T2 at one hour. T3 treatment significantly enhanced Na+K+-ATPase activity while T2 decreased it except by low dose at one hour. Both T3 and T2 treatment influenced the activities of enzymes of lipid synthesis in a dose and time dependent manner emphasising a short-term effect of these thyroid hormones in Anabas.
Asunto(s)
Diyodotironinas/farmacología , Peces/metabolismo , Metabolismo de los Lípidos , Triyodotironina/farmacología , Animales , Diyodotironinas/administración & dosificación , Femenino , Glucosafosfato Deshidrogenasa/metabolismo , Hidroximetilglutaril-CoA Reductasas/metabolismo , Isocitrato Deshidrogenasa/metabolismo , Cinética , Hígado/efectos de los fármacos , Hígado/enzimología , Malato Deshidrogenasa/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Triyodotironina/administración & dosificaciónRESUMEN
Loss of the positive force-frequency relationship is a characteristic finding in failing hearts. The mechanisms of this change are not well understood. Myocardial infarction (MI) was induced in rabbits to produce left ventricular (LV) dysfunction. Beginning 1 day after MI, a subgroup of rabbits received diiodothyropropionic acid (DITPA) (3.75 mg x kg(-1) x day(-1) sc) for 3 wk. We measured contractions, Ca(2+) transients, action potentials, and sarcoplasmic reticulum (SR) Ca(2+) content at different stimulation rates in single LV myocytes. The shortening-frequency relationship was markedly flattened in MI myocytes compared with control myocytes. In addition, Ca(2+) transients, action potentials, and contractions were prolonged. Myocytes from DITPA-treated MI rabbits had preserved inotropic responses to increased stimulation rate and normal duration of action potentials and Ca(2+) transients. SR Ca(2+) content increased significantly when stimulation rate was increased from 0.5 to 2.0 Hz in control myocytes but did not change significantly in MI myocytes. Myocytes from DITPA-treated MI rabbits had a greater frequency-dependent increase in SR Ca(2+) content compared with the untreated MI rabbits. Thus single myocytes from infarcted rabbit hearts have frequency-dependent abnormalities of contractility, Ca(2+) cycling, and action potential repolarization. The flattened contraction-frequency relationship can be partially explained by an attenuation of the normal enhancement of SR Ca(2+) content that occurs when stimulation rate is increased. Chronic DITPA administration after MI largely prevents the development of these abnormalities.
Asunto(s)
Diyodotironinas/farmacología , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/fisiopatología , Propionatos/farmacología , Potenciales de Acción , Animales , Calcio/metabolismo , Tamaño de la Célula , Diyodotironinas/administración & dosificación , Ecocardiografía , Estimulación Eléctrica , Masculino , Miocardio/patología , Propionatos/administración & dosificación , Conejos , Retículo Sarcoplasmático/metabolismoRESUMEN
Recent data have suggested that the iodothyronine, 3,5-diiodo-l-thyronine (T2), has selective thyromimetic activity. In vivo, T2 has been shown to suppress TSH levels at doses that do not produce significant peripheral manifestations of thyroid hormone activity. Furthermore, T2 has been shown to produce smaller increments in peripheral indices of thyroid status than does T3, when doses resulting in equivalent suppression of circulating TSH are compared. We have assessed the selective thyromimetic activity of T2 in vivo and in vitro, and performed in vitro studies to assess the potential molecular basis for these selective properties. T2 was 100-fold less potent than T3 in stimulating GH mRNA levels in GH3 cells. In contrast, the iodothyronines were almost equivalent in their ability to downregulate TRbeta2 mRNA levels in this cell line. Both 3,3'-diiodo-L-thyronine and thyronine exhibited no significant thyromimetic effects on either process. In vivo, doses of T2 and T3 that were equivalent in their induction of hepatic malic enzyme (ME) mRNA did not produce equivalent suppression of circulating TSH, with T2 being only 27% as effective as T3. T2 was up to 500-fold less potent than T3 in displacing [125I]-T3 from in vitro translated specific nuclear receptors (TRs) and GH3 cell nuclear extracts. Electrophoretic mobility shift assays, assessing the ability of T2 to produce dissociation of TRbeta1 homodimers from inverted palindrome T3 response elements, indicated that T2 was also 1000-fold less potent than T3 in this respect. These data confirm that T2 has significant thyromimetic activity, and that this activity is selective both in vivo and in vitro. However, there are no data to support a selective central effect, T2 being relatively more potent in stimulating hepatic ME mRNA than in suppression of TSH in vivo. The basis for this differential thyromimetic activity is not selective affinity of the different TR isoforms for T2, or divergent properties of T2 in competitive binding and functional assays in vitro.
Asunto(s)
Diyodotironinas/administración & dosificación , Diyodotironinas/farmacología , Hormonas Tiroideas/agonistas , Animales , Línea Celular , Dimerización , Regulación de la Expresión Génica/efectos de los fármacos , Hormona del Crecimiento/efectos de los fármacos , Hormona del Crecimiento/genética , Inyecciones Intraperitoneales , Malato Deshidrogenasa/genética , Masculino , Especificidad de Órganos , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Unión Proteica , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Hormona Tiroidea/efectos de los fármacos , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/metabolismo , Tirotropina/sangreRESUMEN
BACKGROUND: An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. METHODS AND RESULTS: To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 micrograms/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21 +/- 2 and 26 +/- 2 mm Hg, respectively, vs 34 +/- 3 mm Hg, P < .05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P < .05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in tau, the time constant of LV pressure decline (17.5 +/- 1.0 vs 22.2 +/- 1.7 milliseconds, P < .05) and a larger absolute value for -dP/dtmax (-4561 +/- 361 vs -3346 +/- 232 mm Hg/s, P < .05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P > .05). CONCLUSIONS: The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.