RESUMEN
Thyroid hormones (THs) control a wide range of physiological functions essential for metabolism, growth, and differentiation. On a molecular level, TH action is exerted by nuclear receptors (TRs), which function as ligand-dependent transcription factors. Among several TR isoforms, the function of TRα2 remains poorly understood as it is a splice variant of TRα with an altered C-terminus that is unable to bind T3. This review highlights the molecular characteristics of TRα2, proposed mechanisms that regulate alternative splicing and indications pointing towards an antagonistic function of this TR isoform in vitro and in vivo. Moreover, remaining knowledge gaps and major challenges that complicate TRα2 characterization, as well as future strategies to fully uncover its physiological relevance, are discussed.
Asunto(s)
Empalme Alternativo , Hormonas Tiroideas , Isoformas de Proteínas/genética , Receptores Citoplasmáticos y Nucleares , Receptores de Hormona Tiroidea/genéticaRESUMEN
Thyroid hormones (THs) and TH receptor-beta (TRß) reduce hepatic triglycerides, indicating a therapeutic potential for TH analogs in liver steatosis. To avoid adverse extrahepatic, especially TRα-mediated effects such as tachycardia and bone loss, TH analogs with combined TRß and hepatocyte specificity are desired. MGL-3196 is a new TH analog that supposedly meets these criteria. Here, we characterize the thyromimetic potential of MGL-3196 in cell-based assays and address its cellular uptake requirements. We studied the contribution of liver-specific organic anion transporters (OATP)1B1 and 1B3 to MGL-3196 action. The TR isoform-specific efficacy of MGL-3196 compared with 3,5,3'-triiodothyronine (T3) was determined with luciferase assays and gene expression analysis in OATP1B1 and OATP1B3 and TRα- or TRß-expressing cells and in primary murine hepatocytes (PMHs) from wild-type and TRß knockout mice. We measured the oxygen consumption rate to compare the effects of MGL-3196 and T3 on mitochondrial respiration. We identified OATP1B1 as the primary transporter for MGL-3196. MGL-3196 had a high efficacy (90% that of T3) in activating TRß, while the activation of TRα was only 25%. The treatment of PMHs with T3 and MGL-3196 at EC50 resulted in a similar induction of Dio1 and repression of Serpina7. In HEK293 cells stably expressing OATP1B1, MGL-3196 had comparable effects on mitochondrial respiration as T3. These data indicate that MGL-3196's hepatic thyromimetic action, the basis for its therapeutic use, results from a combination of hepatocyte-specific transport by OATP1B1 and the selective activation of TRß over TRα.
Asunto(s)
Hepatocitos , Receptores de Hormona Tiroidea , Humanos , Ratones , Animales , Receptores de Hormona Tiroidea/metabolismo , Células HEK293 , Hepatocitos/metabolismo , Triyodotironina/farmacología , Triyodotironina/metabolismo , Receptores beta de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/metabolismo , Isoformas de Proteínas/metabolismo , Ratones Noqueados , CadáverRESUMEN
Hypothyroidism has been shown to reduce infarct size in rats, but the underlying mechanisms are unclear. We used isolated pressure-constant perfused hearts of control, hypothyroid and hyperthyroid mice and measured infarct size, functional parameters and phosphorylation of key molecules in cardioprotective signaling with matched heart rate. Compared with controls, hypothyroidism was cardioprotective, while hyperthyroidism was detrimental with enlarged infarct size. Next, we asked how thyroid hormone receptor α (TRα) affects ischemia/reperfusion (IR) injury. Thus, canonical and noncanonical TRα signaling was investigated in the hearts of (i) mice lacking TRα (TRα0), (ii) with a mutation in TRα DNA-binding domain (TRαGS) and (iii) in hyperthyroid TRα0 (TRα0hyper) and TRαGS mice (TRαGShyper). TRα0 mouse hearts were protected against IR injury. Furthermore, infarct size was reduced in the hearts of TRαGS mice that lack canonical TRα signaling but maintain noncanonical TRα action. Hyperthyroidism did not increase infarct size in TRα0 and TRαGS mouse hearts. These cardioprotective effects were not associated with increased phosphorylation of key proteins of RISK, SAFE and eNOS pathways. In summary, chronic hypothyroidism and the lack of canonical TRα signaling are cardioprotective in IR injury and protection is not due to favorable changes in hemodynamics.
Asunto(s)
Hipertiroidismo , Hipotiroidismo , Daño por Reperfusión , Ratas , Ratones , Animales , Hipotiroidismo/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Receptores alfa de Hormona Tiroidea/metabolismo , Hipertiroidismo/metabolismo , Hemodinámica , Daño por Reperfusión/metabolismo , Infarto , Miocardio/metabolismoRESUMEN
Introduction: Thyroid hormones (THs) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases is still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Methods: Mice at the age of 12 months underwent TAC and received T4 or anti-thyroid medication in drinking water over the course of 4 weeks after induction of left ventricular pressure overload. Results: T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis, and interstitial fibrosis), and mortality. This is surprising because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. Comparing the gene expression of deiodinases (Dio) 2 and 3 and TH receptor alpha (TRα) 1 and the dominant-negative acting isoform TRα2 between young and aged mice revealed that aged mice exhibited a higher expression of TRα2 and Dio3, while expression of Dio2 was reduced compared with young mice. These changes in Dio2 and 3 expressions might lead to reduced TH availability in the hearts of 12-month-old mice accompanied by reduced TRα action due to higher TRα2. Discussion: In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure-induced cardiac damage. This observation seems to be the result of an altered expression of deiodinases and TRα isoforms, thus suggesting that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.
Asunto(s)
Insuficiencia Cardíaca , Hipertensión , Ratones , Animales , Cardiomegalia/etiología , Cardiomegalia/metabolismo , Insuficiencia Cardíaca/etiología , Miocitos Cardíacos/metabolismo , Hormonas Tiroideas/metabolismo , Hipertensión/complicacionesRESUMEN
Background: Stimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). The aim of this study was to determine in vivo which TH receptor (TR)-α or ß-and which mode of TR action-canonical gene expression or DNA-binding independent noncanonical action-mediate these effects. Methods: We compared global TRα and TRß knockout mice (TRαKO; TRßKO) with wild-type (WT) mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRαGS; TRßGS). Hearts were studied with echocardiography at baseline and after 7 weeks of T3 treatment. Gene expression was measured with real-time polymerase chain reaction. Heart rate was recorded with radiotelemetry transmitters for 7 weeks in untreated, hypothyroid, and T3-treated mice. Results: T3 induced ventricular hypertrophy in WT and TRßKO mice, but not in TRαKO mice. Hypertrophy was also induced in TRαGS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRαGS mice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3 treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRαKO mice, demonstrating that TRß could compensate for absence of TRα. Conclusions: T3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRß could substitute for canonical but not noncanonical TRα action.
Asunto(s)
Cardiomegalia , Frecuencia Cardíaca , Ratones Noqueados , Receptores alfa de Hormona Tiroidea , Receptores beta de Hormona Tiroidea , Triyodotironina , Animales , Masculino , Ratones , Cardiomegalia/metabolismo , Cardiomegalia/genética , Hipotiroidismo/metabolismo , Hipotiroidismo/genética , Isoformas de Proteínas/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores beta de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/metabolismoRESUMEN
Thyroid hormone (TH) effects are mediated through TH receptors (TRs), TRα1, TRß1, and TRß2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely unknown. The aim of this study was to attribute physiological effects to the TR isoforms and their canonical and noncanonical signaling. We conducted multiparameter phenotyping in male and female TR knockout mice (TRαKO, TRßKO), mice with disrupted canonical signaling due to mutations in the TR DNA binding domain (TRαGS, TRßGS), and their wild-type littermates. Perturbations in senses, especially hearing (mainly TRß with a lesser impact of TRα), visual acuity, retinal thickness (TRα and TRß), and in muscle metabolism (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization, or increased anxiety-related behavior were only observed in TRαKO but not TRαGS mice. Noncanonical TRα action improved energy utilization and prevented hyperphagia observed in female TRαKO mice. In summary, by examining the phenotypes of TRα and TRß knockout models alongside their DNA binding-deficient mutants and wild-type counterparts, we could establish that the noncanonical actions of TRα and TRß play a crucial role in modulating sensory, behavioral, and metabolic functions and, thus, contribute to the spectrum of physiological TH effects.
Asunto(s)
Ratones Noqueados , Fenotipo , Receptores alfa de Hormona Tiroidea , Receptores beta de Hormona Tiroidea , Animales , Femenino , Masculino , Receptores alfa de Hormona Tiroidea/genética , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores beta de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/metabolismo , Ratones , Transducción de Señal/genética , Hormonas Tiroideas/metabolismo , Ratones Endogámicos C57BLRESUMEN
The hypothalamic pituitary thyroid axis is a major regulator of many differentiation processes, including adipose tissue. However, it remains unclear whether and how thyroid hormone (TH) signaling contributes to preadipocyte commitment and differentiation into mature adipocytes. Here, we show a cell-autonomous effect of TH on the transcriptional regulation of zinc finger protein 423 (Zfp423), an early adipogenic determination factor, in murine adipose depots. Mechanistically, binding of the unliganded TH receptor to a negative TH responsive element within the Zfp423 promoter activates transcriptional activity that is reversed upon TH binding. Zfp423 upregulation is associated with increased GFP+ preadipocyte recruitment in stromal vascular fraction isolated from white fat of hypothyroid Zfp423GFP reporter mice. RNA sequencing identified Zfp423-driven gene programs that are modulated in response to TH during adipogenic differentiation. Collectively, we identified Zfp423 as a key molecule that integrates TH signaling into the regulation of adipose tissue plasticity.
Asunto(s)
Adipocitos , Proteínas de Unión al ADN , Animales , Ratones , Adipocitos/metabolismo , Adipogénesis/fisiología , Tejido Adiposo/metabolismo , Diferenciación Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Obesidad/metabolismo , Hormonas Tiroideas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
CONTEXT: 3,5,3'-L-triiodothyronine (T3) is a potent inducer of hepatocyte proliferation via the Wnt/ß-catenin signaling pathway. Previous studies suggested the involvement of rapid noncanonical thyroid hormone receptor (TR) ß signaling, directly activating hepatic Wnt/ß-catenin signaling independent from TRß DNA binding. However, the mechanism by which T3 increases Wnt/ß-catenin signaling in hepatocytes has not yet been determined. OBJECTIVE: We aimed to determine whether DNA binding of TRß is required for stimulation of hepatocyte proliferation by T3. METHODS: Wild-type (WT) mice, TRß knockout mice (TRßâKO), and TRß mutant mice with either specifically abrogated DNA binding (TRßâGS) or abrogated direct phosphatidylinositol 3 kinase activation (TRßâ147F) were treated with T3 for 6 hours or 7 days. Hepatocyte proliferation was assessed by Kiel-67 (Ki67) staining and apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Activation of ß-catenin signaling was measured in primary murine hepatocytes. Gene expression was analyzed by microarray, gene set enrichment analysis (GSEA), and quantitative reverse transcription polymerase chain reaction. RESULTS: T3 induced hepatocyte proliferation with an increased number of Ki67-positive cells in WT and TRßâ147F mice (9.2%â ±â 6.5% and 10.1%â ±â 2.9%, respectively) compared to TRßâKO and TRßâGS mice (1.2%â ±â 1.1% and 1.5%â ±â 0.9%, respectively). Microarray analysis and GSEA showed that genes of the Wnt/ß-catenin pathway-among them, Fzd8 (frizzled receptor 8) and Ctnnb1 (ß-catenin)-were positively enriched only in T3-treated WT and TRßâ147F mice while B-cell translocation gene anti-proliferation factor 2 was repressed. Consequently, expression of Ccnd1 (CyclinD1) was induced. CONCLUSIONS: Instead of directly activating Wnt signaling, T3 and TRß induce key genes of the Wnt/ß-catenin pathway, ultimately stimulating hepatocyte proliferation via CyclinD1. Thus, canonical transcriptional TRß action is necessary for T3-mediated stimulation of hepatocyte proliferation.
Asunto(s)
Proliferación Celular/fisiología , Hepatocitos/fisiología , Receptores beta de Hormona Tiroidea/fisiología , Triyodotironina/farmacología , Animales , Sitios de Unión/genética , Proliferación Celular/efectos de los fármacos , Ciclina D1/fisiología , ADN/metabolismo , Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hipotiroidismo , Masculino , Ratones , Ratones Noqueados , Ratones Mutantes , Mutación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Receptores beta de Hormona Tiroidea/genética , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/genéticaRESUMEN
Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification. Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks. Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation. Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.
RESUMEN
Thyroid hormone (TH) metabolism and cellular TH action are influenced by ageing. To investigate the response to thyroxine (T4) overtreatment, a kinetic study was conducted in young and aged mice with chronic hyperthyroidism and hormone withdrawal. Five and 22 months old male mice were treated with T4 or PBS over 5 weeks, followed by observation for up to 12 days. Serial analysis was performed for thyroid function parameters, transcript levels of TH target genes, deiodinase type 1 (DIO1) activity as well as serum lipids at 12, 24, 72, 144, 216, and 288 h after cessation of T4 administration. Higher FT3 concentrations and higher renal DIO1 activities were noted in aged mice 12 h after T4 withdrawal and marked thyroid-stimulating hormone elevation was found in aged mice after 12 days compared to respective controls. A biphasic expression pattern occurred for TH target genes in all organs and a hypothyroid organ state was observed at the end of the study, despite normalization of TH serum concentrations after 72 h. In line with this, mirror-image kinetics were detected for serum cholesterol and triglycerides in aged and young mice. Recovery from TH overtreatment in mice involves short- and medium-term adaption of TH metabolism on systemic and organ levels. Increased renal DIO1 activity may contribute to higher T3 concentrations and prolonged thyrotoxicosis followed by hypothyroidism in an aged-mouse organism. Translation of these findings in the clinical setting seems warranted and may lead to better management of hyperthyroidism and prevention of T4 overtreatment in aged patients.
Asunto(s)
Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/metabolismo , Tiroxina/farmacología , Factores de Edad , Animales , Biomarcadores , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Hipotiroidismo/sangre , Hipotiroidismo/etiología , Metabolismo de los Lípidos , Lípidos/sangre , Masculino , Ratones , Especificidad de Órganos , Sobretratamiento , Tiroxina/administración & dosificación , Tiroxina/efectos adversos , Resultado del Tratamiento , Triyodotironina/sangre , Triyodotironina/metabolismoRESUMEN
Background: Serum thyroid state in older adults correlates with extended longevity. We hypothesized that age impacts not only systemic but also organ-specific thyroid state and response to thyroxine (T4). Methods: Young (3 months) and old (23 months) male mice were analyzed at baseline and after acute T4 challenge. Age effects on circulating thyrotropin (TSH) and thyroid hormone (TH) concentrations, transcript expression in the pituitary and thyroid were compared with organ-specific responses characterized by hepatic and cardiac content of TH and TH metabolites and expression of TH-target genes, as well as hepatic deiodinase 1 activity. Results: Circulating TH concentrations and hepatic and cardiac TH content were lower in old versus young mice. After injection with T4, conversion of T4 to triiodothyronine was decreased in old mice while TH transport in liver and heart was not affected. Organ-specific TH response was augmented in old mice in liver but not heart, indicating age- and tissue-specific sensitivity to TH. A compensatory increase of thyroid stimulating hormone subunit beta expression in the pituitary and increased serum TSH concentrations, but reduced expression of thyroid differentiation markers were found in old mice. Conclusions: We suggest that a reduced activity of the aged thyroid is responsible for the systemic low TH state in old mice. Further, divergent TH metabolism and tissue response in liver and heart occur after T4 treatment in an aged organism. These rodent data are in agreement with a much narrower window for T4 substitution in the older adults to avoid overtreatment.
Asunto(s)
Envejecimiento/metabolismo , Envejecimiento/patología , Glándula Tiroides/crecimiento & desarrollo , Glándula Tiroides/metabolismo , Tiroxina/metabolismo , Tiroxina/farmacología , Animales , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Sistema Hipotálamo-Hipofisario , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Hipófisis/crecimiento & desarrollo , Hipófisis/metabolismo , Glándula Tiroides/patología , Hormonas Tiroideas/sangre , Tirotropina/sangre , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
Clinical manifestation of hyperthyroidism and hypothyroidism vary with age, with an attenuated, oligosymptomatic presentation of thyroid dysfunction (TD) in older patients. We asked, whether in rodents TD phenotypes are influenced by age and whether this involves changes in systemic and/or organ thyroid hormone (TH) signaling. Chronic hyper- or hypothyroidism was induced in male mice at different life stages (5, 12, and 20 months). TH excess resulted in pronounced age-specific body weight changes (increase in youngest and decrease in old mice), neither explained by changes in food intake (similar increase at all ages), nor by thermogenic gene expression in brown adipose tissue (BAT) or TH serum concentrations. Relative increase in body temperature and activity were more pronounced in old compared to young hyperthyroid mice. An attenuated hypothyroid state was found in old mice for locomotor activity and in heart and BAT on functional (less bradycardia) and gene expression level (heart and BAT). In contrast, decrease in body weight was pronounced in old hypothyroid mice. Thus, age has divergent impact on features of TD in mice, whereby effects on highly complex systems, such as energy homeostasis are not proportional to serum TH state, in contrast to organ-specific responses in heart and BAT.
Asunto(s)
Envejecimiento/fisiología , Hipertiroidismo/fisiopatología , Hipotiroidismo/fisiopatología , Hormonas Tiroideas/sangre , Tejido Adiposo/metabolismo , Animales , Temperatura Corporal/fisiología , Expresión Génica , Corazón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/fisiología , FenotipoRESUMEN
Background: Radioiodine refractory dedifferentiated thyroid cancer is a major clinical challenge. Anaplastic lymphoma kinase (ALK) mutations with increased ALK activity, especially fusion genes, have been suggested to promote thyroid carcinogenesis, leading to development of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma. To determine the oncogenic potential of increased ALK activity in thyroid carcinogenesis in vivo, we studied mice with thyrocyte-specific expression of a constitutively active ALK mutant. Methods: Mice carrying a Cre-activated allele of a constitutively active ALK mutant (F1174L) were crossed with mice expressing tamoxifen-inducible Cre recombinase (CreERT2) under the control of the thyroglobulin (Tg) gene promoter to achieve thyrocyte-specific expression of the ALK mutant (ALKF1174L mice). Survival, thyroid hormone serum concentration, and tumor development were recorded. Thyroids and lungs were studied histologically. To maintain euthyroidism despite dedifferentiation of the thyroid, a cohort was substituted with levothyroxine (LT4) through drinking water. Results: ALKF1174L mice developed massively enlarged thyroids, which showed an early loss of normal follicular architecture 12 weeks after tamoxifen injection. A significant decrease in Tg and Nkx-2.1 expression as well as impaired thyroid hormone synthesis confirmed dedifferentiation. Histologically, the mice developed a carcinoma resembling human PDTC with a predominantly trabecular/solid growth pattern and an increased mitotic rate. The tumors showed extrathyroidal extension into the surrounding strap muscles and developed lung metastases. Median survival of ALKF1174L mice was significantly reduced to five months after tamoxifen injection. Reduced Tg expression and loss of follicular structure led to hypothyroidism with elevated thyrotropin (TSH). To test whether TSH stimulation played a role in thyroid carcinogenesis, we kept ALKF1174L mice euthyroid by LT4 substitution. These mice developed PDTC with identical histological features compared with hypothyroid mice, demonstrating that PDTC development was due to increased ALK activity and not dependent on TSH stimulation. Conclusion: Expression of a constitutively activated ALK mutant in thyroids of mice leads to development of metastasizing thyroid cancer resembling human PDTC. These results demonstrate in vivo that increased ALK activity is a driver mechanism in thyroid carcinogenesis.
Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma/genética , Desdiferenciación Celular/genética , Hipotiroidismo/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias de la Tiroides/genética , Animales , Carcinoma/patología , Carcinoma/secundario , Hipotiroidismo/etiología , Ratones , Invasividad Neoplásica , Tiroglobulina/metabolismo , Neoplasias de la Tiroides/patología , Factor Nuclear Tiroideo 1/metabolismo , Tirotropina/metabolismoRESUMEN
BACKGROUND: Sex and age play a role in the prevalence of thyroid dysfunction (TD), but their interrelationship for manifestation of hyper- and hypothyroidism is still not well understood. Using a murine model, we asked whether sex impacts the phenotypes of hyper- and hypothyroidism at two life stages. METHODS: Hyper- and hypothyroidism were induced by i.p. T4 or MMI/ClO4-/LoI treatment over 7 weeks in 12- and 20-months-old female and male C57BL/6N mice. Control animals underwent PBS treatment (n = 7-11 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination and strength) and serum thyroid hormone (TH) status. RESULTS: Distinct sex impact was found in eu- and hyperthyroid mice, while phenotypic traits of hypothyroidism were similar in male and female mice. No sex difference was found in TH status of euthyroid mice; however, T4 treatment resulted in twofold higher TT4, FT4 and FT3 serum concentrations in adult and old females compared to male animals. Hyperthyroid females consistently showed higher locomotor activity and better coordination but more impairment of muscle function by TH excess at adult age. Importantly and in contrast to male mice, adult and old hyperthyroid female mice showed increased body weight. Higher body temperature in female mice was confirmed in all age groups. No sex impact was found on heart rate irrespective of TH status in adult and old mice. CONCLUSIONS: By comparison of male and female mice with TD at two life stages, we found that sex modulates TH action in an organ- and function-specific manner. Sex differences were more pronounced under hyperthyroid conditions. Importantly, sex-specific differences in features of TD in adult and old mice were not conclusively explained by serum TH status in mice.
Asunto(s)
Hipertiroidismo/fisiopatología , Hipotiroidismo/fisiopatología , Caracteres Sexuales , Envejecimiento/fisiología , Animales , Temperatura Corporal/fisiología , Peso Corporal/fisiología , Ingestión de Líquidos/fisiología , Ingestión de Alimentos/fisiología , Femenino , Frecuencia Cardíaca/fisiología , Masculino , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Hormonas Tiroideas/sangreRESUMEN
Protocols for induction of hyperthyroidism in mice are highly variable and mostly involve short-term thyroid hormone (TH) treatment. In addition, little is known about a possible influence of sex on experimental TH manipulation. Here we analyzed the efficacy of intraperitoneal vs. oral levothyroxine (T4) administration to induce chronic hyperthyroidism in male and female mice and asked which T4 dosing intervals are required to achieve stable organ thyrotoxicosis. T4 was administered intraperitoneally or orally over a period of 6/7 weeks. Assessment included monitoring of body weight, TH serum concentrations, and serial quantitative TH target gene expression analysis in liver and heart. Our results show that both intraperitoneal and oral T4 treatment are reliable methods for induction of chronic hyperthyroidism in mice. Thereby T4 injection intervals should not exceed 48 h and oral levothyroxine should be administered continuously during experiments and up to sacrifice to ensure a hyperthyroid organ state. Furthermore, we found a sex-dependent variation in levothyroxine-induced TH serum state, with significantly higher T4 concentrations in female mice, while expression of investigated classical TH responsive genes in liver and heart did not vary with animal's sex. In summary, our study shows that common approaches for rendering rodents thyrotoxic can also be used for induction of chronic hyperthyroidism in male and female mice. Thereby T4 dosing intervals are critical as are read-out parameters to verify a chronic thyrotoxic organ state.
Asunto(s)
Modelos Animales de Enfermedad , Hipertiroidismo/inducido químicamente , Tiroxina , Animales , Femenino , Hipertiroidismo/sangre , Masculino , Ratones , Factores SexualesRESUMEN
BACKGROUND: Thyroid dysfunction is more common in the female population, however, the impact of sex on disease characteristics has rarely been addressed. Using a murine model, we asked whether sex has an influence on phenotypes, thyroid hormone status, and thyroid hormone tissue response in hyper- and hypothyroidism. METHODS: Hypo- and hyperthyroidism were induced in 5-month-old female and male wildtype C57BL/6N mice, by LoI/MMI/ClO4 (-) or T4 i.p. treatment over 7 weeks, and control animals underwent sham treatment (N = 8 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination, and strength), liver function, serum thyroid hormone status, and cellular TH effects on gene expression in brown adipose tissue, heart, and liver. RESULTS: Male and female mice showed significant differences in behavioural, functional, metabolic, biochemical, and molecular traits of hyper- and hypothyroidism. Hyperthyroidism resulted in increased locomotor activity in female mice but decreased muscle strength and motor coordination preferably in male animals. Hypothyroidism led to increased water intake in male but not female mice and significantly higher serum cholesterol in male mice. Natural sex differences in body temperature, body weight gain, food and water intake were preserved under hyperthyroid conditions. In contrast, natural sex differences in heart rate disappeared with TH excess and deprivation. The variations of hyper- or hypothyroid traits of male and female mice were not explained by classical T3/T4 serum state. TH serum concentrations were significantly increased in female mice under hyperthyroidism, but no sex differences were found under eu- or hypothyroid conditions. Interestingly, analysis of expression of TH target genes and TH transporters revealed little sex dependency in heart, while sex differences in target genes were present in liver and brown adipose tissue in line with altered functional and metabolic traits of hyper- and hypothyroidism. CONCLUSIONS: These data demonstrate that the phenotypes of hypo- and hyperthyroidism differ between male and female mice and indicate that sex is an important modifier of phenotypic manifestations.