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1.
Int J Mol Sci ; 23(12)2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35742991

RESUMO

The opening of the ATP-sensitive mitochondrial potassium channel (mitok-ATP) is a common goal of cardioprotective strategies in the setting of acute and chronic myocardial disease. The biologically active thyroid hormone (TH), 3-5-3-triiodothyronine (T3), has been indicated as a potential activator of mitoK-ATP but the underlying mechanisms are still elusive. Here we describe a novel role of T3 in the transcriptional regulation of mitoK and mitoSur, the recently identified molecular constituents of the channel. To mimic human ischemic heart damage, we used a rat model of a low T3 state as the outcome of a myocardial ischemia/reperfusion event, and neonatal rat cardiomyocytes (NRCM) challenged with hypoxia or H2O2. Either in the in vivo or in vitro models, T3 administration to recover the physiological concentrations was able to restore the expression level of both the channel subunits, which were found to be downregulated under the stress conditions. Furthermore, the T3-mediated transcriptional activation of mitoK-ATP in the myocardium and NRCM was associated with the repression of the TH-inactivating enzyme, deiodinase 3 (Dio3), and an up-regulation of the T3-responsive miR-133a-3p. Mechanistically, the loss and gain of function experiments and reporter gene assays performed in NRCM, have revealed a new regulatory axis whereby the silencing of Dio3 under the control of miR-133a-3p drives the T3-dependent modulation of cardiac mitoK and mitoSur transcription.


Assuntos
MicroRNAs , Mitocôndrias Cardíacas , Trifosfato de Adenosina/metabolismo , Animais , Peróxido de Hidrogênio/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Mitocôndrias Cardíacas/metabolismo , Canais de Potássio/metabolismo , Ratos , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia
2.
Nat Commun ; 13(1): 3394, 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35697700

RESUMO

The thyroid hormone (TH)-controlled recruitment process of brown adipose tissue (BAT) is not fully understood. Here, we show that long-term treatment of T3, the active form of TH, increases the recruitment of thermogenic capacity in interscapular BAT of male mice through hyperplasia by promoting the TH receptor α-mediated adipocyte progenitor cell proliferation. Our single-cell analysis reveals the heterogeneous nature and hierarchical trajectory within adipocyte progenitor cells of interscapular BAT. Further analyses suggest that T3 facilitates cell state transition from a more stem-like state towards a more committed adipogenic state and promotes cell cycle progression towards a mitotic state in adipocyte progenitor cells, through mechanisms involving the action of Myc on glycolysis. Our findings elucidate the mechanisms underlying the TH action in adipocyte progenitors residing in BAT and provide a framework for better understanding of the TH effects on hyperplastic growth and adaptive thermogenesis in BAT depot at a single-cell level.


Assuntos
Tecido Adiposo Marrom , Tri-Iodotironina , Adipócitos/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Proliferação de Células , Hiperplasia/metabolismo , Masculino , Camundongos , Receptores dos Hormônios Tireóideos/metabolismo , Termogênese , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia
3.
Sci Rep ; 12(1): 8852, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35614155

RESUMO

Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective ß1-adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone) accentuates the ability of T3 to stimulate ERK1/2 phosphorylation and proliferative signaling by inhibiting expression of the nuclear phospho-ERK1/2-specific phosphatase, dual-specificity phosphatase-5. While short-duration metoprolol plus T3 therapy generates new heart muscle in healthy mice, in mice with myocardial infarction-induced left ventricular dysfunction and pathological remodeling, it remuscularizes the heart, restores contractile function and reverses chamber dilatation; outcomes that are enduring. If the beneficial effects of metoprolol plus T3 are replicated in humans, this therapeutic strategy has the potential to definitively address ischemic heart failure.


Assuntos
Infarto do Miocárdio , Disfunção Ventricular Esquerda , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Animais , Metoprolol/farmacologia , Metoprolol/uso terapêutico , Camundongos , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia , Disfunção Ventricular Esquerda/patologia , Remodelação Ventricular
4.
Int J Mol Sci ; 23(9)2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35563180

RESUMO

Skin exposure is considered a potentially significant but little-studied pathway for PolyChlorinated Biphenyls uptake in terrestrial reptiles. In this study, a native Italian lizard, Podarcis siculus, was exposed to PCBs-contaminated soil for 120 days. Tissues distribution of PCBs, thyroid hormone levels, and thyroid histo-physiopathology were examined. The accumulation of PCBs in skin, plasma, liver, kidney, and brain were highest at 120 days. The alteration of triiodothyronine (T3) and thyroxine (T4) levels after different concentrations and times to exposure of PCBs was accompanied by the changes in the hormones involved in the hypothalamus-pituitary-thyroid (HPT) axis, namely Thyrotropin Releasing Hormone (TRH) and Thyroid Stimulating Hormone (TSH). Moreover, hepatic levels of deiodinase II (5'ORDII) and content of T3 were positively correlated to exposure to PCBs. These results indicated that in lizards, PCBs exposure through the skin has the potential to disrupt the thyroid endocrine system. Overall, the observed results indicate that PCBs could be associated with changes in thyroid homeostasis in these reptiles, through direct interactions with the metabolism of T4 and T3 through the HPT axis or indirect interactions with peripheral deiodination.


Assuntos
Lagartos , Bifenilos Policlorados , Animais , Masculino , Bifenilos Policlorados/toxicidade , Solo , Glândula Tireoide/metabolismo , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo
5.
Ecotoxicol Environ Saf ; 237: 113510, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35468440

RESUMO

Nitrite in the aquatic environment potentially disturbs thyroid hormone (TH) homeostasis in peripheral tissues, but little is known about TH metabolism in the intestine. This study investigated the serum concentrations of THs and thyroid-stimulating hormone (TSH) as well as the activity of intestinal iodothyronine deiodinases (IDs) of grass carp (Ctenopharyngodon idellus) exposed to various concentrations of nitrite (0, 8, 25, or 50 mg/L) for 96 h. Acute nitrite exposure significantly altered the triiodothyronine (T3) levels and the morphology of thyroid follicles at 96 h. Thyroxine (T4), free T4 levels and intestinal IDs activities showed an increase trend under nitrite stress. After 96 h exposure, nitrite down-regulated the expressions levels of intestinal Akt1 protein, sugar transporter genes, and thyroid hormone receptor (TR) signaling pathway genes except for tr É‘1 and tr É‘2. Moreover, the expressions levels of pparγ, cpt1α, cd36, fabp2 and fatp4 were down-regulated, whereas fabp6 and lpl were up-regulated in the 50 mg/L exposure group at 96 h. The results indicate that acute nitrite exposure has the potential to disturb the homeostasis of intestinal TH metabolism, which in turn alters TRs genes transcription, down-regulates sugar transporter activities, and promotes the energy expenditure in gut of grass carp.


Assuntos
Carpas , Hormônios Gastrointestinais , Animais , Carpas/metabolismo , Hormônios Gastrointestinais/metabolismo , Homeostase , Iodeto Peroxidase/genética , Nitritos , Açúcares/metabolismo , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo , Tiroxina , Tri-Iodotironina/metabolismo
6.
Gen Comp Endocrinol ; 323-324: 114047, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35472316

RESUMO

Thyroid hormone (TH) is a critical signalling molecule for all vertebrate organisms, playing a crucial role in postembryonic development. The best-studied mechanism of TH response is through modulating gene expression, however TH's involvement in coordinating the early steps in the TH signal transduction pathway is still poorly understood. The American bullfrog, Rana [Lithobates] catesbeiana, is a useful model to study these early responses as tadpole post-embryonic development in the form of metamorphosis of the tadpole into a frog can be experimentally induced by TH exposure. The rate of TH-induced metamorphosis can be modulated by temperature where sufficiently cold temperatures (5 °C) completely halt precocious metamorphosis. Interestingly, when premetamorphic tadpoles exposed to exogenous THs at 5 °C are shifted to permissive temperatures (24 °C), their metamorphic rate exceeds that of TH-exposed tadpoles at the permissive temperature. This suggests that a molecular memory of TH exposure is retained at 5 °C even after THs are cleared at this low temperature. However, the molecular memory machinery is poorly understood. Herein we use RNA-seq analysis to identify potential components of the molecular memory in cultured tail fin that allows for the recapitulation of the molecular memory phenomenon. Eighty-one gene transcripts were TH-responsive at 5 °C compared to matched controls indicating that the molecular memory is more complex than previously thought. Many of these transcripts encode transcription factors including thyroid hormone-induced B/Zip, thibz, and a novel krüppel-like factor family member, klfX. Actinomycin D and cycloheximide treatment had no effect on their TH induction suggesting that a change in transcription or translation is not required. Rather a change in RNA stability may be a possible mechanism contributing to the molecular memory. The ability to manipulate temperature and TH response in cultured organs provide an exciting opportunity to further elucidate the early TH signalling mechanisms during postembryonic development.


Assuntos
Metamorfose Biológica , Hormônios Tireóideos , Animais , Regulação da Expressão Gênica no Desenvolvimento , Larva/metabolismo , Rana catesbeiana/metabolismo , Ranidae/metabolismo , Transdução de Sinais , Temperatura , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismo
7.
Endocrinology ; 163(5)2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35238380

RESUMO

Adaptive thermogenesis in small mammals and infants takes place in brown adipose tissue (BAT). Heat is produced via uncoupling protein 1 (UCP1)-mediated uncoupling between oxidation of energy substrates and adenosine 5'-triphosphate synthesis. Thyroid hormone (TH) signaling plays a role in this process. The deiodinases activate thyroxine (T4) to 3,5,3'-triiodothyronine (T3) (D2) or inactivate T4 and T3 to 3,3,5'-triiodothyronine and T2 (D3), respectively. Using a mouse model with selective inactivation of Dio3 in BAT (flox-Dio3 × UCP1-cre = BAT-D3KO), we now show that knocking out D3 resulted in premature exposure of developing brown adipocytes (embryonic days 16.5-18.5) to T3 signaling, leading to an earlier expression of key BAT genes, including Cidea, Cox8b, Dio2, Ucp1, and Pgc1α. Adult BAT-D3KO mice exhibited increased expression of 1591 genes as assessed by RNA sequencing, including 19 gene sets related to mitochondria, 8 related to fat, and 8 related to glucose homeostasis. The expression of 243 genes was changed by more than 1.5-fold, 36 of which play a role in metabolic/thermogenic processes. BAT-D3KO mice weigh less and exhibit smaller white adipocyte area, but maintain normal energy expenditure at room temperature (22 °C) and in the cold (4 °C). They also defend their core temperature more effectively and do not lose as much body weight when exposed to cold. We conclude that the coordinated actions of Dio3 in the embryonic BAT define the timing and intensity of T3 signaling during brown adipogenesis. Enhanced T3 signaling during BAT embryogenesis (Dio3 inactivation) results in selective life-long modifications in the BAT transcriptome.


Assuntos
Tecido Adiposo Marrom , Iodeto Peroxidase , Tecido Adiposo Marrom/metabolismo , Animais , Humanos , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Masculino , Mamíferos/genética , Termogênese/genética , Transcriptoma , Tri-Iodotironina/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
8.
J Immunol Res ; 2022: 4075522, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35224111

RESUMO

OBJECTIVE: Autoimmune thyroid diseases (AITD), mainly Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common organ-specific autoimmune diseases characterized by circulating antibodies and lymphocyte infiltration. Follicular helper T (Tfh) cell dysregulation is involved in the development of autoimmune pathologies. We aimed to explore the role of intrathyroidal and circulating Tfh cells in patients with GD and HT. METHODS: Ultrasound-guided thyroid fine-needle aspiration (FNA) was conducted in 35 patients with GD, 40 patients with HT, and 22 patients with nonautoimmune thyroid disease (nAITD). Peripheral blood samples were also obtained from 40 patients with GD, 40 patients with HT, and 40 healthy controls. The frequencies of intrathyroidal and circulating Tfh cells from FNA and peripheral blood samples were assessed by flow cytometry. Additionally, the correlations between the frequencies of the Tfh cells and the levels of autoantibodies and hormones or disease duration were analyzed. RESULTS: The frequency of intrathyroidal CD4+CXCR5+ICOShigh Tfh cells was higher in HT patients than in GD patients. Significant correlations were identified between the percentages of circulating and intrathyroidal Tfh cells and the serum concentrations of thyroid autoantibodies, especially thyroglobulin antibodies (TgAb), in AITD. Intrathyroidal CD4+CXCR5+ICOShigh Tfh cells were positively correlated with free triiodothyronine (FT3) in HT patients but negatively correlated with FT3 in GD patients. In addition, HT patients with a longer disease duration had an increased frequency of intrathyroidal CD4+CXCR5+ICOShigh and CD4+CXCR5+PD-1+ Tfh cells. In contrast, in the GD patients, a longer disease duration did not affect the frequency of intrathyroidal CD4+CXCR5+ICOShigh but was associated with a lower frequency of CD4+CXCR5+PD-1+ Tfh cells. CONCLUSIONS: Our data suggest that intrathyroidal Tfh cells might play a role in the pathogenesis of AITD and they are potential immunobiomarkers for AITD.


Assuntos
Doença de Graves/imunologia , Doença de Hashimoto/imunologia , Células T Auxiliares Foliculares/imunologia , Glândula Tireoide/imunologia , Adulto , Autoanticorpos/sangue , Biomarcadores/metabolismo , Progressão da Doença , Feminino , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Tireoglobulina/imunologia , Tri-Iodotironina/metabolismo
9.
Gen Comp Endocrinol ; 318: 113989, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35151725

RESUMO

To assess the effect of polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) on thyroid hormone [TH: thyroxine (T4) and triiodothyronine (T3)] secretion, the concentrations of iodothyronine deiodinases (DIO1, DIO2, DIO3), and mRNA expression of genes involved in TH synthesis (TSHR, NIS, TPO, TG), metabolism (DIO1, DIO2, DIO3), and transport (OATP1C1, MCT8, MCT10, LAT1), chicken thyroid explants were incubated in medium supplemented with TSH (250 mU/ml), PCB118, PCB153, 4-OH-PCB107, and 3-OH-PCB153 (0.5 × 10-8 M), and TSH together with each PCB and OH-PCB. The results of the in vitro experiment revealed that, except for 4-OH-PCB107, all applied PCBs and OH-PCBs inhibited basal and TSH-stimulated T4 secretion. Moreover, they increased basal and reduced TSH-stimulated T3 secretion. PCBs and OH-PCBs decreased the TSH-stimulated TSHR expression. Following PCB and OH-PCB exposure, significant changes in mRNA expression of NIS, TPO, and TG were observed. PCBs and OH-PCBs affected DIO1 and DIO3 transcript levels and protein abundances of each DIO. Furthermore, PCB-dependent effects on OATP1C1, MCT8, and MCT10 mRNA expression were found. In conclusion, both PCB118 and PCB153 and their OH-PCBs affect TH synthesis and deiodination processes in the chicken thyroid gland and influence TH transport across the thyrocyte membrane. In addition, the effects of PCBs and OH-PCBs depended mainly on the type of PCB congener and the exposure time. These results indicate that not only parental PCBs but also OH-PCBs are hazardous for the thyroid gland and may disrupt its endocrine function. Further studies are necessary to explain a mechanism of PCB and OH-PCB action in the avian thyroid gland.


Assuntos
Bifenilos Policlorados , Animais , Galinhas/metabolismo , Bifenilos Policlorados/metabolismo , Bifenilos Policlorados/farmacologia , Glândula Tireoide/metabolismo , Tiroxina/metabolismo , Tiroxina/farmacologia , Tri-Iodotironina/metabolismo
10.
Nat Commun ; 13(1): 61, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013249

RESUMO

The thyroglobulin (TG) protein is essential to thyroid hormone synthesis, plays a vital role in the regulation of metabolism, development and growth and serves as intraglandular iodine storage. Its architecture is conserved among vertebrates. Synthesis of triiodothyronine (T3) and thyroxine (T4) hormones depends on the conformation, iodination and post-translational modification of TG. Although structural information is available on recombinant and deglycosylated endogenous human thyroglobulin (hTG) from patients with goiters, the structure of native, fully glycosylated hTG remained unknown. Here, we present the cryo-electron microscopy structure of native and fully glycosylated hTG from healthy thyroid glands to 3.2 Å resolution. The structure provides detailed information on hormonogenic and glycosylation sites. We employ liquid chromatography-mass spectrometry (LC-MS) to validate these findings as well as other post-translational modifications and proteolytic cleavage sites. Our results offer insights into thyroid hormonogenesis of native hTG and provide a fundamental understanding of clinically relevant mutations.


Assuntos
Microscopia Crioeletrônica , Tireoglobulina/química , Tireoglobulina/metabolismo , Bócio , Humanos , Iodetos , Iodo , Modelos Moleculares , Conformação Proteica , Proteólise , Tireoglobulina/genética , Glândula Tireoide/metabolismo , Hormônios Tireóideos/química , Hormônios Tireóideos/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo
11.
FASEB J ; 36(2): e22141, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34981562

RESUMO

In peripheral tissues, triiodothyronine (T3) production and consequent thyroid hormone actions are mainly regulated by iodothyronine deiodinases (DIOs) classified into 3 types: D1, D2, and D3. We aimed to investigate the effects of peripheral DIOs on thyroid hormone economy independent of the hypothalamus-pituitary-thyroid axis. We cloned coding sequences of human DIOs with FLAG-tag and HiBiT-tag sequences into a pcDNA3.1 vector. To obtain full-length proteins, we modified these vectors by cloning the selenocysteine insertion sequence of each DIO (SECIS vectors). Western blot analyses and HiBiT lytic assay using HEK293T cells revealed that SECIS vectors expressed full-length proteins with substantial activity. Subsequently, in vivo transfections of pLIVE-based SECIS vectors into male C57BL/6J mice were performed by hydrodynamic gene delivery to generate mice overexpressing DIOs predominantly in the liver (D1, D2, and D3 mice). After 7 days from transfections, mice were analyzed to clarify phenotypes. To summarize, serum thyroid hormone levels did not change in D1 mice but D2 mice had higher serum free T3 levels. D3 mice developed hypothyroidism with higher serum reverse T3 (rT3) levels. Transfections with levothyroxine administration suggested that thyroid hormone action was upregulated in D2 mice. Our DIO-overexpressing mice provided insights on the physiological properties of upregulated DIOs: D2 augments local thyroid hormone action and recruits T3 into the circulation: D3 decreases circulating T3 and T4 levels with elevated rT3, leading to consumptive hypothyroidism. As D3 mice are expected to be a novel hypothyroidism model, they can contribute to progress in the field of thyroid hormone economy and action.


Assuntos
Iodeto Peroxidase/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Linhagem Celular , Células HEK293 , Humanos , Hipotireoidismo/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Glândula Tireoide/metabolismo , Tri-Iodotironina/metabolismo
12.
Drug Metab Dispos ; 50(4): 508-517, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35046065

RESUMO

Increased disposition of thyroid hormones is a way that xenobiotics may alter thyroid homeostasis and, in rats, produce thyroid follicular adenoma/carcinoma. This capacity is historically attributed to induction of thyroxine (T4) glucuronidation by UDP-glycosyltransferase (UGT) enzymes, and cytochrome P450 induction is often a surrogate. However, gaps exist in correlating the effectiveness of certain chemical inducers at increasing T4 glucuronidation with decreases in systemic T4 and resulting increases in thyroid-stimulating hormone. With the identification of other key inducible drug processing genes and proteins involved in hepatic disposition of thyroid hormones, including uptake (e.g., organic anion transporter polypeptides) and efflux (e.g., multidrug resistance proteins) transporters, data exist that support transporters as additional target sites of induction. These data are reviewed herein and indicate an increase in hepatic uptake of thyroid hormones, as well as increased biliary excretion of iodothyronine conjugates, represent critical activities that differentiate inducer effectiveness in disrupting thyroid hormones in rats. Increased membrane transport of thyroid hormones, likely in conjunction with induced glucuronidation of thyroid hormone (triiodothyronine more relevant than T4), provide a better indication of thyroid disrupting potential than consideration of UGT induction alone. Because coordinate regulation of these targets is inconsistent among inducers belonging to various classes and among species, and there are disparities between in vitro assays and in vivo responses, further work is required to identify specific and relevant inducible thyroid hormone uptake transporters. Data from Mrp2-null animals have contributed key information, yet the contributions of efflux transport (canalicular and basolateral) to the mechanism of individual, effective inducers also require further study. SIGNIFICANCE STATEMENT: Key advances in understanding the target sites for altered disposition of thyroid hormones have occurred in the last 2 decades to better inform potential sites of action of inducing chemicals. Ultimately, the knowledge of inducible thyroid hormone transport into and out of liver, beyond induction of glucuronidation, should be considered and applied to screening and risk assessment paradigms when assessing an inducer's potential to alter thyroid homeostasis in nonclinical species and humans.


Assuntos
Glucuronosiltransferase , Hormônios Tireóideos , Animais , Glucuronosiltransferase/metabolismo , Fígado/metabolismo , Ratos , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/farmacologia , Tireotropina/metabolismo , Tireotropina/farmacologia , Tiroxina/metabolismo , Tiroxina/farmacologia , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-34756986

RESUMO

Phenanthrene, a polycyclic aromatic hydrocarbon (PAH), is one of the endocrine disrupting chemicals (EDCs). The present study aimed to evaluate the effects of phenanthrene on histophysiology of thyroid in Arabian seabream (Acanthopagrus arabicus). In this regards, different concentrations of phenanthrene (2, 20 and 40 pg/gbw) were injected to Acanthopagrus arabicus and changes in thyroid tissue structure and the serum levels of triiodothyronine (T3) and Thyroxine (T4) were assessed. The experiment lasted 21 days. Alterations in thyroid tissue structure and T3 and T4 serum levels also were assessed in Acanthopagrus arabicus caught from different stations of the Persian Gulf (Jafari, Samail, Arvand, Zangi, Bahrakan). In addition, the concentration of phenanthrene was measured in the fish muscle and sediment samples from the stations. Phenanthrene concentration reached the maximum level in the muscle of all injected fish after 4 days and then decreased by the end of the experiment. The highest and lowest concentrations of phenanthrene were recorded in the fish muscle and sediment samples collected from Jafari and Bahrakan, respectively. The levels of T3 and T4 decreased dose dependently in phenanthrene-injected fish up to day 7 and then increased by the end of the experiment. The serum level of T3 and T4 in fish collected from different stations was as follows: Jafari

Assuntos
Perciformes/metabolismo , Fenantrenos/toxicidade , Glândula Tireoide/efeitos dos fármacos , Animais , Masculino , Músculo Esquelético , Glândula Tireoide/metabolismo , Tiroxina/sangue , Tiroxina/metabolismo , Tri-Iodotironina/sangue , Tri-Iodotironina/metabolismo , Poluentes Químicos da Água/toxicidade
14.
Dev Growth Differ ; 64(1): 48-58, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34862790

RESUMO

Thyroid hormone (T3) affects many diverse physiological processes such as metabolism, organogenesis, and growth. The two highly related frog species, diploid Xenopus tropicalis and pseudo tetraploid Xenopus laevis, have been used as models for analyzing the effects of T3 during vertebrate development. T3 regulates T3-inducible gene transcription through T3 receptor (TR)-binding to T3-response elements (TREs). We have previously identified sperm associated antigen 7 (spag7) as a candidate T3 target gene that is potentially involved in adult stem cell development and/or proliferation during intestinal metamorphosis. To investigate whether T3 regulates spag7 directly at the transcriptional level via TR, we first conducted qRT-PCR to analyze its expression during natural and T3-induced metamorphosis and found that spag7 was up-regulated during natural metamorphosis in the intestine, tail, brain and hindlimb, peaking at the climax of metamorphosis in all those organs, and upon T3 treatment of premetamorphic tadpoles. Next, we demonstrated that an intronic TRE in spag7, first identified through bioinformatic analysis, could bind to TR in vitro and in vivo during metamorphosis. A dual luciferase assay utilizing a reconstituted frog oocyte transcription system showed that the TRE could mediate promoter activation by liganded TR. These results indicate that spag7 expression is directly regulated by T3 through the TRE in the first intron during metamorphosis, implicating a role for spag7 early during T3-regulated tissue remodeling and resorption.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Metamorfose Biológica , Animais , Íntrons , Masculino , Metamorfose Biológica/genética , Elementos de Resposta , Espermatozoides , Hormônios Tireóideos , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia , Xenopus/genética , Xenopus/metabolismo , Xenopus laevis/genética , Xenopus laevis/metabolismo
15.
Cryobiology ; 105: 63-70, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34863702

RESUMO

Thyroid hormone was involved in gene expression and functional regulation in various signal pathways. Cold stress can increase triiodothyronine (T3) level in the blood. The aim of this study was to investigate the effect of T3 on HSP70 expression and apoptosis in Sertoli cells (SCs) under cold stress in vitro culture at 26 °C, and provide a theoretical and practical basis for improving the reproductive efficiency of bulls in cold areas. SCs were treated with different cold stress duration and different T3 concentrations for pre-screening. HSP70 inhibitor was added later, and the apoptotic rate was measured using flow cytometry. The expression of HSP70 and the main genes of mitochondrial apoptosis pathway were determined by means of real-time PCR and western-blot, respectively. The localization of HSP70 was assessed by immunofluorescence. The results showed that cold stress (26 °C, 6 h) played an inductive role in SCs apoptotic rate (P < 0.01) and the transfer of HSP70 into the nucleus. 100 nM T3 further promoted HSP70 expression and its transfer into the nucleus, which significantly inhibited the expression of vital genes (cyt-c, Caspase-9 and Caspase-3) in mitochondrial pathway (P < 0.05). Subsequently, higher survival and lower apoptotic rates of SCs (P < 0.01) were observed. When T3 and HSP70 inhibitor were added together, the expression of cyt-c, Caspase-9 and Caspase-3 were inhibited (P < 0.05), and then the declining apoptotic rate increased again (P < 0.01). In conclusion, T3 can regulate HSP70 expression and translocation to mediate mitochondrial apoptosis pathway to inhibit SCs apoptosis induced by cold stress.


Assuntos
Resposta ao Choque Frio , Células de Sertoli , Animais , Apoptose , Caspase 3/metabolismo , Caspase 9 , Bovinos , Criopreservação/métodos , Citocromos c/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Masculino , Transdução de Sinais , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/farmacologia , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia
16.
J Clin Endocrinol Metab ; 107(2): 450-461, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34570185

RESUMO

CONTEXT: Thyroid hormone (TH) is crucial for the adaptation to cold. OBJECTIVE: To evaluate the effect of hyperthyroidism on resting energy expenditure (REE), cold-induced thermogenesis (CIT) and changes in body composition and weight. METHODS: This was a prospective cohort study at the endocrine outpatient clinic of a tertiary referral center. Eighteen patients with overt hyperthyroidism were included. We measured REE during hyperthyroidism, after restoring euthyroid TH levels and after 3 months of normal thyroid function. In 14 of the 18 patients, energy expenditure (EE) was measured before and after a mild cold exposure of 2 hours and CIT was the difference between EEcold and EEwarm. Skin temperatures at 8 positions were recorded during the study visits. Body composition was assessed by dual X-ray absorption. RESULTS: Free thyroxine (fT4) and free triiodothyronine (fT3) decreased significantly over time (fT4, P = .0003; fT3, P = .0001). REE corrected for lean body mass (LBM) decreased from 42 ±â€…6.7 kcal/24 hour/kg LBM in the hyperthyroid to 33 ±â€…4.4 kcal/24 hour/kg LBM (-21%, P < .0001 vs hyperthyroid) in the euthyroid state and 3 months later to 33 ±â€…5.2 kcal/24 hour/kg LBM (-21%, P = .0022 vs hyperthyroid, overall P < .0001). fT4 (P = .0001) and fT3 (P < 0.0001) were predictors of REE. CIT did not change from the hyperthyroid to the euthyroid state (P = .96). Hyperthyroidism led to increased skin temperature at warm ambient conditions but did not alter core body temperature, nor skin temperature after cold exposure. Weight regain and body composition were not influenced by REE and CIT during the hyperthyroid state. CONCLUSION: CIT is not increased in patients with overt hyperthyroidism.


Assuntos
Metabolismo Basal/fisiologia , Hipertireoidismo/metabolismo , Termogênese , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Antagonistas Adrenérgicos/uso terapêutico , Adulto , Idoso , Composição Corporal , Temperatura Baixa/efeitos adversos , Feminino , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Testes de Função Tireóidea , Tiroxina/sangue , Tri-Iodotironina/sangue , Adulto Jovem
17.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34669927

RESUMO

Thyroid hormones (TH) are essential for skeletal development and adult bone homeostasis. Their bioavailability is determined by specific transporter proteins at the cell surface. The TH-specific transporter monocarboxylate transporter 8 (MCT8) was recently reported as a regulator of bone mass in mice. Given that high systemic triiodothyronine (T3) levels in Mct8 knockout (KO) mice are still able to cause trabecular bone loss, alternative TH transporters must substitute for MCT8 function in bone. In this study, we analyzed the skeletal phenotypes of male Oatp1c1 KO and Mct10 KO mice, which are euthyroid, and male Mct8/Oatp1c1 and Mct8/Mct10 double KO mice, which have elevated circulating T3 levels, to unravel the role of TH transport in bone. MicroCT analysis showed no significant trabecular bone changes in Oatp1c1 KO mice at 4 weeks and 16 weeks of age compared with wild-type littermate controls, whereas 16-week-old Mct8/Oatp1c1 double KO animals displayed trabecular bone loss. At 12 weeks, Mct10 KO mice, but not Mct8/Mct10 double KO mice, had decreased trabecular femoral bone volume with reduced osteoblast numbers. By contrast, lack of Mct10 in 24-week-old mice led to trabecular bone gain at the femur with increased osteoblast numbers and decreased osteoclast numbers whereas Mct8/Mct10 double KO did not alter bone mass. Neither Mct10 nor Mct8/Mct10 deletion affected vertebral bone structures at both ages. In vitro, osteoblast differentiation and activity were impaired by Mct10 and Mct8/Mct10-deficiency. These data demonstrate that MCT10, but not OATP1C1, is a site- and age-dependent regulator of bone mass and turnover in male mice.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Osso e Ossos/metabolismo , Animais , Transporte Biológico , Fenômenos Biomecânicos , Osso Esponjoso/metabolismo , Diferenciação Celular , Fêmur/fisiologia , Homeostase , Masculino , Camundongos , Camundongos Knockout , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteócitos/citologia , Fenótipo , Simportadores/metabolismo , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismo , Microtomografia por Raio-X
18.
Thyroid ; 32(3): 326-335, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34937426

RESUMO

Background: A recent genome-wide association study identified the SLC17A4 locus associated with circulating free thyroxine (T4) concentrations. Human SLC17A4, being widely expressed in the gastrointestinal tract, was characterized as a novel triiodothyronine (T3) and T4 transporter. However, apart from the cellular uptake of T3 and T4, transporter characteristics are currently unknown. In this study, we delineated basic transporter characteristics of this novel thyroid hormone (TH) transporter. Methods: We performed a broad range of well-established TH transport studies in COS-1 cells transiently overexpressing SLC17A4. We studied cellular TH uptake in various incubation buffers, TH efflux, and the inhibitory effects of different TH metabolites and known inhibitors of other TH transporters on SLC17A4-mediated TH transport. Finally, we determined the effect of tunicamycin, a pharmacological inhibitor of N-linked glycosylation, and targeted mutations in Asn residues on SLC17A4 function. Results: SLC17A4 induced the cellular uptake of T3 and T4 by ∼4 times, and of reverse (r)T3 by 1.5 times over control cells. The uptake of T4 by SLC17A4 was Na+ and Cl- independent, stimulated by low extracellular pH, and reduced by various iodothyronines and metabolites thereof, particularly those that contain at least three iodine moieties irrespective of the presence of modification at the alanine side chain. None of the classical TH transporter inhibitors studied attenuated SLC17A4-mediated TH transport. SLC17A4 also facilitates the efflux of T3 and T4, and to a lesser extent of 3,3'-diiodothyronine (T2). Immunoblot studies on lysates of transfected cells cultured in absence or presence of tunicamycin indicated that SLC17A4 is subject to N-linked glycosylation. Complementary mutational studies identified Asn66, Asn75, and Asn90, which are located in extracellular loop 1, as primary targets. Conclusions: Our studies show that SLC17A4 facilitates the transport of T3 and T4, and less efficiently rT3 and 3,3'-T2. Further studies should reveal the physiological role of SLC17A4 in TH regulation.


Assuntos
Estudo de Associação Genômica Ampla , Tiroxina , Humanos , Proteínas de Membrana Transportadoras , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I , Hormônios Tireóideos/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Tunicamicina
19.
Artigo em Inglês | MEDLINE | ID: mdl-34936295

RESUMO

Glioma is one of the most common types of primary intracranial tumors. The relationship between triiodothyronine (T3) and glioma is not clear. This study aimed to investigate the effect of T3 on the proliferation of glioma cells and its mechanism. Cell viability was analyzed by cell counting kit 8 assay. Flow cytometry analysis was used to detect cell apoptosis and cell cycle. Thyroid hormone receptor α (THRA) and thyroid hormone receptor ß (THRB) were silenced by transfecting si-THRA and si-THRB plasmids into HS683 and A172 glioma cells. Western blot was performed to assess the protein expressions. The results indicated that triiodothyronine (T3) affected the viability, apoptosis and cell cycle of HS683 and A172 glioma cells. Cell apoptosis was significantly inhibited in si-THRA and si-THRB experimental groups. Moreover, knockdown of THRA and THRB reversed the G1 and G2 phase arrest led by T3 and induced an up-regulation of cyclin D1 expression. The phosphorylated extracellular signal-regulated kinase (p-ERK), p-AKT, and phosphorylated signal transducer and activator of transcription (p-STAT3) proteins were markedly increased by inhibiting THRA and THRB in HS683 and A172 glioma cells. T3 affected apoptosis and cell cycle of glioma cells through regulating THRA and THRB expressions. THRA and THRB may affect glioma development through regulating, at least partially, the mitogen-activated protein kinase (MAPK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways.


Assuntos
Apoptose/genética , Senescência Celular/genética , Glioma/fisiopatologia , Receptores alfa dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/genética , Tri-Iodotironina/metabolismo , Linhagem Celular Tumoral , Inativação Gênica , Humanos , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo
20.
Nat Commun ; 12(1): 6845, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34824246

RESUMO

Maternal obesity (MO) predisposes offspring to obesity and metabolic disorders but little is known about the contribution of offspring brown adipose tissue (BAT). We find that MO impairs fetal BAT development, which persistently suppresses BAT thermogenesis and primes female offspring to metabolic dysfunction. In fetal BAT, MO enhances expression of Dio3, which encodes deiodinase 3 (D3) to catabolize triiodothyronine (T3), while a maternally imprinted long noncoding RNA, Dio3 antisense RNA (Dio3os), is inhibited, leading to intracellular T3 deficiency and suppression of BAT development. Gain and loss of function shows Dio3os reduces D3 content and enhances BAT thermogenesis, rendering female offspring resistant to high fat diet-induced obesity. Attributing to Dio3os inactivation, its promoter has higher DNA methylation in obese dam oocytes which persists in fetal and adult BAT, uncovering an oocyte origin of intergenerational obesity. Overall, our data uncover key features of Dio3os activation in BAT to prevent intergenerational obesity and metabolic dysfunctions.


Assuntos
Tecido Adiposo Marrom/metabolismo , Obesidade/genética , RNA Longo não Codificante/genética , Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Adipogenia , Tecido Adiposo Marrom/citologia , Animais , Diferenciação Celular , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Dieta Ocidental/efeitos adversos , Metabolismo Energético , Feminino , Impressão Genômica , Iodeto Peroxidase/metabolismo , Camundongos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade Materna/genética , Obesidade Materna/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Gravidez , RNA Longo não Codificante/metabolismo , Termogênese , Fatores de Transcrição/metabolismo , Tri-Iodotironina/metabolismo
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