Nuclear Thyroid Hormone Receptors Research Articles

A Cardiac MicroRNA Governs Systemic Energy Homeostasis by Regulation of MED13

Obesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders.

Thyroid hormone regulation of APP (β-amyloid precursor protein) gene expression in brain and brain cultured cells

We have previously shown that the thyroid hormone triiodothyronine negatively regulates the transcriptional activity of the β-amyloid precursor protein gene (APP) in cultured murine neuroblastoma cells, by a mechanism that involves binding of the nuclear thyroid hormone receptor (TR) to DNA sequences located within the first exon of the gene. In this report we present results showing that the thyroid hormones also repress the expression of APP in human neuroblastoma cells and in primary cultures of rat neurons. In addition, and in agreement with the results obtained in cultured cells, APP messenger RNA and protein levels are significantly higher in the brain of hypothyroid rats and mice, and also in Alzheimer-related brain regions dissected from KO mice lacking TRs. These results show that binding of the thyroid hormones to their nuclear receptors mediate their repressive effect on APP gene expression in vivo.

Binding Properties of Thyroxine to Nuclear Extract from Sea Urchin Larvae

We previously reported that thyroid hormones are involved in the formation of the adult rudiment and adult-type skeleton in sea urchin larvae, as well as in the resorption of larval tissues. In the present study, to search for the presence of thyroid hormone receptor in sea urchin larvae, we performed a ligand-binding assay between radiolabeled thyroid hormones and nuclear extracts from the larvae of the sea urchin Hemicentrotus pulcherrimus. The presence of binding sites with a high affinity to thyroxine (T4) was detected in the nuclear extract, but not in the cytoplasmic fraction. The dissociation constants for the T4 binding to the nuclear extracts were estimated to be about 18 pM from the mesenchyme-blastula stage to the four-armed pluteus stage. The quantity of T4 binding sites in the nuclear extracts increased during larval development. These results suggest that the binding affinity to T4 in the nuclear extracts was caused by a putative nuclear thyroid hormone receptor in sea urchin larvae.

History of the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases: Impact on Understanding and Treatment of Diseases of the Thyroid Gland

History of the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases: Impact on Understanding and Treatment of Diseases of the Thyroid Gland

Dickkopf 4 positively regulated by the thyroid hormone receptor suppresses cell invasion in human hepatoma cells

Thyroid hormone (T(3)) mediates cellular growth, development, and differentiation by binding to the nuclear thyroid hormone receptor (TR). Recent studies suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma (HCC) independent from other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein, antagonizes the Wnt signal pathway. In this study, we demonstrate that T(3) may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA (mRNA) and protein levels. DKK4 was down-regulated in 67.5% of HCC cancerous tissues. The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues. Further, TR and DKK4 expression levels were positively correlated in both normal and cancerous specimens by tissue array analysis. In function assays, stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro. Conversely, knocking down DKK4 restores cell invasiveness. DKK4-expressing J7 clones showed increased degradation of β-catenin, but down-regulation of CD44, cyclin D1, and c-Jun. To investigate the effect of DKK4 and TR on tumor growth in vivo, we established a xenograft of J7 cells in nude mice. J7-DKK4 and J7-TRα1 overexpressing mice, which displayed growth arrest, lower lung colony formation index, and smaller tumor size than in control mice, supporting an inhibitory role of DKK4 in tumor progression. Taken together, these data suggest that the TR/DKK4/Wnt/β-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR.

Aorta-Derived Mesoangioblasts Differentiate into the Oligodendrocytes by Inhibition of the Rho Kinase Signaling Pathway

Mesoangioblasts are vessel-derived stem cells that differentiate into mesodermal derivatives. We have isolated postnatal aorta-derived mesoangioblasts (ADMs) that differentiate into smooth, skeletal, and cardiac muscle, and adipocytes, and regenerate damaged skeletal muscle in a murine model for Duchenne muscular dystrophy. We report that the marker profile of ADM is similar to that of mesoangioblasts isolated from embryonic dorsal aorta, postnatal bone marrow, and heart, but distinct from mesoangioblasts derived from skeletal muscle. We also demonstrate that ADM differentiate into myelinating glial cells. ADM localize to peripheral nerve bundles in regenerating muscles and exhibit morphology and marker expression of mature Schwann cells, and myelinate axons. In vitro, ADM spontaneously express markers of oligodendrocyte progenitors, including the chondroitin sulphate proteoglycan NG2, nestin, platelet-derived growth factor (PDGF) receptor α, the A2B5 antigen, thyroid hormone nuclear receptor α, and O4. Pharmacological inhibition of Rho kinase (ROCK) initiated process extension by ADM, and when combined with insulin-like growth factor 1, PDGF, and thyroid hormone, enhanced ADM expression of oligodendrocyte precursor markers and maturation into the oligodendrocyte lineage. ADM injected into the right lateral ventricle of the brain migrate to the corpus callosum, and cerebellar white matter, where they express components of myelin. Because ADM differentiate or mature into cell types of both mesodermal and ectodermal origin, they may be useful for treatment of a variety of degenerative diseases, or repair and regeneration of multiple cell types in severely damaged tissue.

Neither bovine somatotropin nor growth hormone-releasing factor alters expression of thyroid hormone receptors in liver and mammary tissues

Physiological effects of thyroid hormones are mediated primarily by binding of triiodothyronine to specific nuclear receptors. Organ-specific changes in production of triiodothyronine from its prohormone, thyroxine, have been hypothesized to target the action of thyroid hormones on the mammary gland and play a role in mediating or augmenting a galactopoietic response to bovine somatotropin (bST). Additionally, tissue responsiveness to thyroid hormones may be altered by changes in the number or affinity of nuclear receptors for thyroid hormones. In the present study, effects of bST and bovine growth hormone-releasing factor (bGRF) on thyroid hormone receptors in liver and mammary gland were studied. Lactating Holstein cows received continuous infusions of bST or bGRF for 63 d or served as uninfused controls. Nuclei were isolated from harvested mammary and liver tissues and incubated with [125I]-triiodothyronine. Treatments did not alter the capacity or affinity of specific binding sites for triiodothyronine in liver or mammary nuclei. Evaluation of transcript abundance for thyroid hormone receptors showed that isoforms of thyroid hormone receptor or retinoid receptor (which may influence thyroid receptor action) expressed in the mammary gland were not altered by bST or bGRF treatment. Data do not support the hypothesis that administration of bST or bGRF alters sensitivity of mammary tissue by changing expression of thyroid hormone receptors.

Brain regional thyroid hormone status and Dio3: where genetics, epigenetics and psychiatric vulnerability meet

Thyroid hormones (TH), thyroxine (T4) and triiodothyronine (T3), are critical for metabolic homeostasis as well as brain development and functioning. The bio-active T3, metabolized from T4, binds to a family of nuclear thyroid hormone receptors (TR) and thereby regulates the transcription of neurodevelopmental genes. Expression of the a and b TR sub-families in the brain is isoform and region specific

Transcriptional regulation by nonclassical action of thyroid hormone

Thyroid hormone (TH) is essential for normal development, growth and metabolism. Its effects were thought to be principally mediated through triiodothyronine (T3), acting as a ligand for the nuclear TH receptors (TRs) α and β residing on thyroid hormone response elements (TREs) in the promoter of TH target genes. In this classical model of TH action, T3 binding to TRs leads to recruitment of basal transcription factors and increased transcription of TH responsive genes.Recently, the concept of TH action on gene expression has become more diverse and now includes nonclassical actions of T3 and T4: T3 has been shown to activate PI3K via the TRs, which ultimately increases transcription of certain genes, e.g. HIF-1α. Additionally, both T3 and thyroxine (T4) can bind to a membrane integrin, αvβ3, which leads to activation of the PI3K and MAPK signal transduction pathways and finally also increases gene transcription, e.g. of the FGF2 gene. Therefore, these initially nongenomic, nonclassical actions seem to serve as additional interfaces for transcriptional regulation by TH. Aim of this perspective is to summarize the genes that are currently known to be induced by nonclassical TH action and the mechanisms involved.

T3 AND 3,5-T2 PARTICIPATE IN TILAPIA GROWTH THROUGH A DIFFERENT SIGNALING PATHWAY

Event Abstract Back to Event T3 AND 3,5-T2 PARTICIPATE IN TILAPIA GROWTH THROUGH A DIFFERENT SIGNALING PATHWAY Pamela Navarrete-Ramírez1, Patricia Villalobos1, Carlos Valverde-R1 and Aurea Orozco1* 1 Universidad Nacional Autonoma de Mexico, Neurobiología Celular y Molecular, Instituto de Neurobiologia, Mexico Considered the biologically active thyroid hormone (TH); triiodothyronine (T3) actions involve TH-dependent de novo gene transcription and are mediated by TH nuclear receptors (TR). Recent studies from our laboratory have shown that in some teleosts, 3, 5-T2, a TH formed through the outer-ring deiodination of T3 is also bioactive. The effects of 3, 5-T2 appear to be mediated by a different isoform of TRβ1 that contains a 9 amino acid insert in its ligand binding domain, and which we have denominated long TRβ1 (L-TRβ1). To further understand 3, 5-T2 bioactivity and its action mechanism, we used body growth as an endpoint and analyzed 3, 5-T2 participation in this process, as well as the possible differential regulation of the signaling pathway of both iodothyronines. To this end, we treated tilapia fingerlings (~0.8 ±0.02 g) by immersion with 1.3 nM of one of the following TH: T3, 3, 5-T2, the prohormone T4 and the inactive isomer rT3. A negative control group was treated with methimazole (MMI: 4.5 mM). All experimental groups were treated for 8 hours, three times week for a month. We recorded growth (body weight) and measured the expression of GH, IGF-1, S-TRβ1 (short TRβ1: without the 9 aa insert) and L-TRβ1. These genes are involved in growth and/or are part of TH signaling pathway. Growth rate of fish exposed to T4, T3 or 3, 5-T2 was significantly higher (average of 26%) than that of the control (untreated) group (p <0.001), while growth rate of tilapia exposed to rT3 was similar to control fish. Tilapia treated with MMI showed the lowest growth rate (p <0.001). Intrahepatic expression of GH and IGF-1 was up-regulated by both, 3, 5-T2 and T3, while the expression L-TRβ1 increased only in the 3, 5-T2-treated fish and S- TRβ1 was up-regulated only by T3. Our results support the notion that although T3 and 3, 5-T2 seem to participate in the growth process, the signaling pathways of both hormones are regulated differently. Acknowledgements Tilapias were kindly provided by SAGARPA, Querétaro, Qro., and kept in laboratory facilities by Miguel Angel Maqueda. This work was partially supported by: CONACYT 080420 and PAPIIT IN203409. Keywords: 3, 5-T2, Growth, Thyroid Hormones Conference: NASCE 2011: The inaugural meeting of the North American Society for Comparative Endocrinology, Ann Arbor, United States, 13 Jul - 16 Jul, 2011. Presentation Type: Poster Topic: Growth and aging Citation: Navarrete-Ramírez P, Villalobos P, Valverde-R C and Orozco A (2011). T3 AND 3,5-T2 PARTICIPATE IN TILAPIA GROWTH THROUGH A DIFFERENT SIGNALING PATHWAY. Front. Endocrinol. Conference Abstract: NASCE 2011: The inaugural meeting of the North American Society for Comparative Endocrinology. doi: 10.3389/conf.fendo.2011.04.00090 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 20 Jul 2011; Published Online: 09 Aug 2011. * Correspondence: Dr. Aurea Orozco, Universidad Nacional Autonoma de Mexico, Neurobiología Celular y Molecular, Instituto de Neurobiologia, Querétaro, Querétaro, 76230, Mexico, aureao@unam.mx Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Pamela Navarrete-Ramírez Patricia Villalobos Carlos Valverde-R Aurea Orozco Google Pamela Navarrete-Ramírez Patricia Villalobos Carlos Valverde-R Aurea Orozco Google Scholar Pamela Navarrete-Ramírez Patricia Villalobos Carlos Valverde-R Aurea Orozco PubMed Pamela Navarrete-Ramírez Patricia Villalobos Carlos Valverde-R Aurea Orozco Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The binding of synthetic triiodo l-thyronine analogs to human transthyretin: Molecular basis of cooperative and non-cooperative ligand recognition

Transthyretin (TTR) is a tetrameric β-sheet-rich transporter protein directly involved in human amyloid diseases. Several classes of small molecules can bind to TTR delaying its amyloid fibril formation, thus being promising drug candidates to treat TTR amyloidoses. In the present study, we characterized the interactions of the synthetic triiodo L-thyronine analogs and thyroid hormone nuclear receptor TRβ-selective agonists GC-1 and GC-24 with the wild type and V30M variant of human transthyretin (TTR). To achieve this aim, we conducted in vitro TTR acid-mediated aggregation and isothermal titration calorimetry experiments and determined the TTR:GC-1 and TTR:GC-24 crystal structures. Our data indicate that both GC-1 and GC-24 bind to TTR in a non-cooperative manner and are good inhibitors of TTR aggregation, with dissociation constants for both hormone binding sites (HBS) in the low micromolar range. Analysis of the crystal structures of TTRwt:GC-1(24) complexes and their comparison with the TTRwt X-ray structure bound to its natural ligand thyroxine (T4) suggests, at the molecular level, the basis for the cooperative process displayed by T4 and the non-cooperative process provoked by both GC-1 and GC-24 during binding to TTR.

Stanniocalcin 1 Induction by Thyroid Hormone Depends on Thyroid Hormone Receptor β and Phosphatidylinositol 3-kinase Activation

Thyroid hormone (TH) mediated changes in gene expression were thought to be primarily initiated by the nuclear TH receptor (TR) binding to a thyroid hormone response element in the promoter of target genes. A recently described extranuclear mechanism of TH action consists of the association of TH-liganded TRβ with phosphatidylinositol 3-kinase (PI3K) in the cytosol and subsequent activation of the PI3K pathway. The aim of this study was to examine the effect of TH, TRβ and PI3K on stanniocalcin 1 (STC1) expression in human cells. We treated human skin fibroblasts with triiodothyronine (T3) in the absence or presence of the PI3K inhibitor LY294002, a dominant negative PI3K subunit, Δp85α, and the protein synthesis inhibitor cycloheximide (CHX). The role of the TRβ was studied in cells from patients with resistance to thyroid hormone (RTH). STC-1 mRNA expression was measured by real-time PCR. We found an induction of STC1 by T3 in normal cells, but less in cells from subjects with RTH (2.7 ± 0.2 vs. 1.6 ± 0.04, P < 0.01). The effect of T3 was completely abrogated by blocking PI3K with LY294002 (3.9 ± 0.5 vs. 0.85 ± 0.5; P < 0.05) and greatly reduced after transfection of a dominant negative PI3K subunit, demonstrating dependency on the PI3K pathway. These results establish STC1 as a TH target gene in humans. Furthermore, we show that STC1 induction by TH depends on both TRβ and PI3K activation.

The T3 Receptor β1 Isoform Regulates UCP1 and D2 Deiodinase in Rat Brown Adipocytes

Brown adipose tissue (BAT) thermogenesis increases when uncoupling protein-1 (UCP1) is activated adrenergically and requires T3. In humans, UCP1 activation in BAT seems involved in body weight maintenance. BAT type 2 deiodinase (D2) increases in response to adrenergic agents, producing the T3 required for UCP1 expression. T3 actions are mediated by thyroid hormone nuclear T3 receptors (TR), TRα and TRβ. Studies in mice suggest that TRβ is required for UCP1 induction, whereas TRα regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T3 vs. specific TRβ1 and TRα1 agonists [GC-1 and CO23] on the adrenergic induction of UCP1 and D2 in cultured rat brown adipocytes. T3 and GC-1 produced similar increases on UCP1, whereas CO23 increased UCP1 only at high doses (50 nm). GC-1 at low doses (0.2-10 nm) was less potent than T3, increasing the adrenergic stimulation of D2 activity and mRNA. At higher doses, GC-1 further stimulated whereas T3 inhibited D2 activity but not D2 mRNA, suggesting posttranscriptional effects. CO23 had no effect on D2 activity but increased D2 mRNA. T3, GC-1, or CO23 by themselves did not increase UCP1 or D2 mRNA. High T3 doses shortened D2 half-life and increased D2 turnover via proteasome, whereas GC-1 did not change D2 stability. The α1- and α2-adrenergic D2 responses increased using high T3 doses. In summary, T3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TRβ1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T3 on TRβ1.

Thyroid Replacement Therapy and Heart Failure

Heart failure (HF) is a major public health and economic problem in Western countries and is one of the most common causes of hospitalization and death. Coronary artery disease is the underlying cause in more than two thirds of chronic HF patients. By 2020, the World Health Organization projects that ischemic heart disease alone will be the most important global cause of morbidity and mortality. The estimated increases in HF-related morbidity and mortality suggest that our understanding of the pathophysiological mechanisms of this syndrome is inadequate. Interest in the role of thyroid hormones (THs) in HF has increased in recent years. The driving considerations can be summarized as follows: (1) the known effects of THs on contractile and relaxation properties of the heart; (2) experimental findings offering strong support for the hypothesis that TH signaling is critical in preserving cardiac structure and performance under normal conditions and after cardiac injury; and (3) evidence that mildly altered TH function is strongly associated with a worsening prognosis in cardiac patients in general and in HF patients in particular. Diastolic function and systolic function are clearly influenced by THs.1 Ventricular contractile function is also influenced by changes in hemodynamic conditions secondary to TH effects on peripheral vascular tone.1 TH homeostasis preserves positive ventricular-arterial coupling, leading to a favorable balance for cardiac work. A study in rats demonstrated that chronic hypothyroidism alone can eventually lead to HF.2 Other studies suggest reduced cardiac tissue triiodothyronine (T3) levels after myocardial infarction (MI) or with development of hypertension by upregulating type 3 deiodinase (D3), which leads to deactivation of T3 and T4 (thyroxine).3–6 This review highlights a growing body of evidence from animal studies and small-scale clinical trials suggesting that low cellular thyroid activity at the cardiac tissue level may adversely affect HF …

The Interaction between Nuclear Receptor Corepressor and Histone Deacetylase 3 Regulates Both Positive and Negative Thyroid Hormone Action in Vivo

Thyroid hormone (TH) plays a critical role in development, growth, and metabolism by binding to nuclear TH receptors to modulate gene expression. In the absence of TH, TH receptors repress genes that are TH-activated by recruiting the nuclear receptor corepressor (NCoR), which exists in a tight complex with histone deacetylase 3 (HDAC3). Here we explored the actions of TH in the deacetylase activating domain mutant (DADm) mouse, whose NCoR-HDAC3 interaction is genetically disrupted. Several TH-activated genes were derepressed in the liver of euthyroid and hypothyroid DADm mice, consistent with the corepressor paradigm and a critical role of the NCoR-HDAC3 interaction in basal repression. The role of corepressors in genes that are down-regulated by TH is less well understood. Remarkably, circulating TSH levels were increased in euthyroid DADm mice, and the pituitary expression of TSHalpha, a classic TH-down-regulated gene, was modestly but significantly elevated regardless of TH status. Thus, the NCoR interaction with HDAC3 modulates expression of both positively- and negatively-regulated genes by TH in vivo.

The Interaction between Nuclear Receptor Corepressor and Histone Deacetylase 3 Regulates Both Positive and Negative Thyroid Hormone Actionin Vivo

Thyroid hormone (TH) plays a critical role in development, growth, and metabolism by binding to nuclear TH receptors to modulate gene expression. In the absence of TH, TH receptors repress genes that are TH-activated by recruiting the nuclear receptor corepressor (NCoR), which exists in a tight complex with histone deacetylase 3 (HDAC3). Here we explored the actions of TH in the deacetylase activating domain mutant (DADm) mouse, whose NCoR-HDAC3 interaction is genetically disrupted. Several TH-activated genes were derepressed in the liver of euthyroid and hypothyroid DADm mice, consistent with the corepressor paradigm and a critical role of the NCoR-HDAC3 interaction in basal repression. The role of corepressors in genes that are down-regulated by TH is less well understood. Remarkably, circulating TSH levels were increased in euthyroid DADm mice, and the pituitary expression of TSHalpha, a classic TH-down-regulated gene, was modestly but significantly elevated regardless of TH status. Thus, the NCoR interaction with HDAC3 modulates expression of both positively- and negatively-regulated genes by TH in vivo.

Regional Decrease of Subcutaneous Adipose Tissue in Patients with Type 2 Familial Partial Lipodystrophy Is Associated with Changes in Thyroid Hormone Metabolism

Familial partial lipodystrophy of the Dunnigan type (FPLD2) presents with a decrease of subcutaneous adipose tissue (SAT) in the limbs and trunk. As thyroid hormones (TH) play an important role in adipogenesis, we studied if SAT from subjects with FPLD2 have changes in the gene expression levels of monocarboxylate transporter 8 (MCT8), a TH transporter, and TH nuclear receptors and in iodothyronine deiodinases (DIOs) expression and activities that could affect TH bioavailability and action in white adipose tissue. Seven subjects with FPLD2 and 10 healthy controls were studied. Two biopsies of SAT were obtained from each subject, one near the umbilicus and the other from the thigh. Expression of MCT8, DIO2, DIO3, THRA1, THRB1, and RXRG mRNAs were quantified by real-time polymerase chain reaction. DIO1 and DIO2 activities in adipose tissue homogenates were determined. Serum thyroid-stimulating hormone and TH levels were measured by chemiluminescence. Subjects with FPLD2 had lower levels of MCT8 mRNA expression in the thigh than in the abdomen SAT, and lower than in the abdomen and thigh SAT from control subjects. FPLD2 subjects also had higher DIO2 expression and activity in the thigh than in the abdomen SAT and higher than in controls. Thigh SAT from subjects with FPLD2 has lower expression of MCT8 and higher DIO2 expression and activity than abdominal SAT, suggesting that changes in local TH metabolism may occur in areas with lipoatrophy. DIO2 expression and activity in SAT suggest that DIO2 can regulate the metabolism and action of TH in human white adipose tissue.

Ontogenetic Profile of the Expression of Thyroid Hormone Receptors in Rat and Human Corpora Cavernosa of the Penis

IntroductionIn the last few years, various studies have underlined a correlation between thyroid function and male sexual function, hypothesizing a direct action of thyroid hormones on the penis.AimTo study the spatiotemporal distribution of mRNA for the thyroid hormone nuclear receptors (TR) α1, α2 and β in the penis and smooth muscle cells (SMCs) of the corpora cavernosa of rats and humans during development.MethodsWe used several molecular biology techniques to study the TR expression in whole tissues or primary cultures from human and rodent penile tissues of different ages.Main Outcome MeasureWe measured our data by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) amplification, Northern blot and immunohistochemistry.ResultsWe found that TRα1 and TRα2 are both expressed in the penis and in SMCs during ontogenesis without development-dependent changes. However, in the rodent model, TRβ shows an increase from 3 to 6 days post natum (dpn) to 20 dpn, remaining high in adulthood. The same expression profile was observed in humans. While the expression of TRβ is strictly regulated by development, TRα1 is the principal isoform present in corpora cavernosa, suggesting its importance in SMC function. These results have been confirmed by immunohistochemistry localization in SMCs and endothelial cells of the corpora cavernosa.ConclusionsThe presence of TRs in the penis provides the biological basis for the direct action of thyroid hormones on this organ. Given this evidence, physicians would be advised to investigate sexual function in men with thyroid disorders. Carosa E, Di Sante S, Rossi S, Castri A, D'Adamo F, Gravina GL, Ronchi P, Kostrouch Z, Dolci S, Lenzi A, and Jannini EA. Ontogenetic profile of the expression of thyroid hormone receptors in rat and human corpora cavernosa of the penis. J Sex Med 2010;7:1381–1390.

Regulation of early spontaneous network activity and GABAergic neurons development by thyroid hormone

Early in development spontaneous activity modulates survival and connectivity of neurons and thus plays a crucial role in the formation of neural networks. The emergence of synchronous activity in cultured neocortical networks initially is driven by large GABAergic interneurons. Here we studied the impact of thyroid hormone on early network development and especially on the development of large GABAergic neurons. Triiodothyronine enhances the frequency of early spontaneous synchronous network activity and an overall increase in network connectivity is indicated by the increased density of glutamatergic and GABAergic synapses. The hormone-induced increase of activity parallels cell type–specific changes in neuronal soma size and cell density, with strong effects on somatic and axonal growth of large GABAergic interneurons. Interestingly, large GABAergic neuron growth is both activity- and hormone-regulated. Blocking neuronal activity by tetrodotoxin or the glutamate receptor blockers D-2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione disodium reveals a direct contribution of triiodothyronine to somatic growth, which also precedes the formation of synchronous network activity. The hormone-mediated effects on spontaneous activity and on large GABAergic neurons growth can be blocked by the nuclear thyroid hormone receptors antagonist 1-850. Thus, our data suggest that triiodothyronine actions result in functional maturation of early cortical networks and cell type–specific structural alterations. The increase in spontaneous activity might initially follow the growth of the large GABAergic neurons, which show an exquisite sensitivity to the presence of thyroid hormones. For the most part, however, the hormone-mediated growth of the GABAergic neurons relies strongly on the maturation of glutamatergic synaptic activity.

The effect of chloral hydrate on the in-vitro T3 binding to adult rat cerebral nuclei

Chloral hydrate is a widely used hypnotic drug for children and animals but the possible interactions of its sedative action and thyroid hormones has not been investigated. In this study the effect of chloral hydrate on the in-vitro binding of triiodothyronine (T3) to cerebral nuclei of adult rats and on the thyroid hormones' synaptosomal and plasma availability were examined. Our results show that during deep anaesthesia caused by a single intraperitoneal administration of chloral hydrate (100 mg kg(-1)), the maximal number of nuclear thyroid hormone receptors (Bmax) and the equilibrium dissociation constant (Kd) were decreased. These changes returned to normal values when rats woke up (2(1/2)h after chloral hydrate administration). Plasma or synaptosomal levels of thyroid hormones were unaffected during chloral hydrate treatment. Our study demonstrates that the nuclear T3 binding in adult rat brain is affected by the sedative action of chloral hydrate.