Selective Inhibition of Genomic and Non-Genomic Effects of Thyroid Hormone Regulates Muscle Cell Differentiation and Metabolic Behavior.

Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are still poorly understood. Skeletal muscle is a classical target tissue for TH, which regulates muscle strength and contraction, as well as energetic metabolism of myofibers. Here we address the different contribution of genomic and non-genomic action of TH in skeletal muscle cells by specifically silencing the deiodinase Dio2 or the ß3-Integrin expression via CRISPR/Cas9 technology. We found that myoblast proliferation is inversely regulated by integrin signal and the D2-dependent TH activation. Similarly, inhibition of the nuclear receptor action reduced myoblast proliferation, confirming that genomic action of TH attenuates proliferative rates. Contrarily, genomic and non-genomic signals promote muscle differentiation and the regulation of the redox state. Taken together, our data reveal that integration of genomic and non-genomic signal pathways finely regulates skeletal muscle physiology. These findings not only contribute to the understanding of the mechanisms involved in TH modulation of muscle physiology but also add insight into the interplay between different mechanisms of action of TH in muscle cells.

Deiodinases: How Nonmammalian Research Helped Shape Our Present View.

Iodothyronine deiodinases are enzymes capable of activating and inactivating thyroid hormones (THs) and have an important role in regulating TH action in tissues throughout the body. Three types of deiodinases (D1, D2, and D3) were originally defined based on their biochemical characteristics. Cloning of the first complementary DNAs in the 1990s (Dio1 in rat and dio2 and dio3 in frog) allowed to confirm the existence of 3 distinct enzymes. Over the years, increasing genomic information revealed that deiodinases are present in all chordates, vertebrates, and nonvertebrates and that they can even be found in some mollusks and annelids, pointing to an ancient origin. Research in nonmammalian models has substantially broadened our understanding of deiodinases. In relation to their structure, we discovered for instance that biochemical properties such as inhibition by 6-propyl-2-thiouracil, stimulation by dithiothreitol, and temperature optimum are subject to variation. Data from fish, amphibians, and birds were key in shifting our view on the relative importance of activating and inactivating deiodination pathways and in showing the impact of D2 and D3 not only in local but also whole body T3 availability. They also led to the discovery of new local functions such as the acute reciprocal changes in D2 and D3 in hypothalamic tanycytes upon photostimulation, involved in seasonal rhythmicity. With the present possibilities for rapid and precise gene silencing in any species of interest, comparative research will certainly further contribute to a better understanding of the importance of deiodinases for adequate TH action, also in humans.

The Deiodinases: Their Identification and Cloning of Their Genes.

In this minireview, we provide a historical outline of the events that led to the identification and characterization of the deiodinases, the recognition that deiodination plays a major role in thyroid hormone action, and the cloning of the 3 deiodinase genes. The story starts in 1820, when it was first determined that elemental iodine was important for normal thyroid function. Almost 100 years later, it was found that the primary active principle of the gland, T4, contains iodine. Once radioactive iodine became available in the 1940s, it was demonstrated that the metabolism of T4 included deiodination, but at the time it was assumed to be merely a degradative process. However, this view was questioned after the discovery of T3 in 1952. We discuss in some detail the events of the next 20 years, which included some failures followed by the successful demonstration that deiodination is indeed essential to normal thyroid hormone action. Finally, we describe how the 3 deiodinases were identified and characterized and their genes cloned.

Thyroid Activating Enzyme, Deiodinase II Is Required for Photoreceptor Function in the Mouse Model of Retinopathy of Prematurity.

Purpose: Retinopathy of prematurity (ROP) is a severe complication of premature infants, leading to vision loss when untreated. Presently, the molecular mechanisms underlying ROP are still far from being clearly understood. This study sought to investigate whether thyroid hormone (TH) signaling contributes to the neuropathology of ROP using the mouse model of ROP to evaluate longitudinal photoreceptor function. Methods: Animals were exposed to hyperoxia from P7 to P12 to induce retinopathy, thereafter the animals were returned to room air (normoxia). The thyroid-activating enzyme type 2 deiodinases (Dio2) knockout (KO) mice and the littermate controls that were exposed to hyperoxia or maintained in room air and were then analyzed. The retinal function was evaluated using electroretinograms (ERGs) at three and seven weeks followed by histologic assessments with neuronal markers to detect cellular changes in the retina. Rhodopsin protein levels were measured to validate the results obtained from the immunofluorescence analyses. Results: In the ROP group, the photoreceptor ERG responses are considerably lower both in the control and the Dio2 KO animals at P23 compared to the non-ROP group. In agreement with the ERG responses, loss of Dio2 results in mislocalized cone nuclei, and abnormal rod bipolar cell dendrites extending into the outer nuclear layer. The retinal function is compromised in the adult Dio2 KO animals, although the cellular changes are less severe. Despite the reduction in scotopic a-wave amplitudes, rhodopsin levels are similar in the adult mice, across all genotypes irrespective of exposure to hyperoxia. Conclusions: Using the mouse model of ROP, we show that loss of Dio2 exacerbates the effects of hyperoxia-induced retinal deficits that persist in the adults. Our data suggest that aberrant Dio2/TH signaling is an important factor in the pathophysiology of the visual dysfunction observed in the oxygen-induced retinopathy model of ROP.

Thyroxine binding to type III iodothyronine deiodinase.

Iodothyronine deiodinases (Dios) are important selenoproteins that control the concentration of the active thyroid hormone (TH) triiodothyronine through regioselective deiodination. The X-ray structure of a truncated monomer of Type III Dio (Dio3), which deiodinates TH inner rings through a selenocysteine (Sec) residue, revealed a thioredoxin-fold catalytic domain supplemented with an unstructured Ω-loop. Loop dynamics are driven by interactions of the conserved Trp207 with solvent in multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin(Trx)-fold domain. Hydrogen bonding interactions of Glu200 with residues conserved across the Dio family anchor the loop's N-terminus to the active site Ser-Cys-Thr-Sec sequence. A key long-lived loop conformation coincides with the opening of a cryptic pocket that accommodates thyroxine (T4) through an I⋯Se halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T4 complex is stabilized by an I⋯O halogen bond between an outer ring iodine and Asp211, consistent with Dio3 selectivity for inner ring deiodination. Non-conservation of residues, such as Asp211, in other Dio types in the flexible portion of the loop sequence suggests a mechanism for regioselectivity through Dio type-specific loop conformations. Cys168 is proposed to attack the selenenyl iodide intermediate to regenerate Dio3 based upon structural comparison with related Trx-fold proteins.

Downregulation of Type 3 Deiodinase in the Hypothalamus During Inflammation.

Background: Inflammation is associated with marked changes in cellular thyroid hormone (TH) metabolism in triiodothyronine (T3) target organs. In the hypothalamus, type 2 deiodinase (D2), the main T3 producing enzyme, increases upon inflammation, leading to an increase in local T3 availability, which in turn decreases thyrotropin releasing hormone expression in the paraventricular nucleus. Type 3 deiodinase (D3), the T3 inactivating enzyme, decreases during inflammation, which might also contribute to the increased T3 availability in the hypothalamus. While it is known that D2 is regulated by nuclear factor κB (NF-κB) during inflammation, the underlying mechanisms of D3 regulation are unknown. Therefore, the aim of the present study was to investigate inflammation-induced D3 regulation using in vivo and in vitro models. Methods: Mice were injected with a sublethal dose of bacterial endotoxin (lipopolysaccharide [LPS]) to induce a systemic acute-phase response. A human neuroblastoma (SK-N-AS) cell line was used to test the involvement of the thyroid hormone receptor alpha 1 (TRα1) as well as the activator protein-1 (AP-1) and NF-κB inflammatory pathways in the inflammation-induced decrease of D3. Results: D3 expression in the hypothalamus was decreased 24 hours after LPS injection in mice. This decrease was similar in mice lacking the TRα. Incubation of SK-N-AS cells with LPS robustly decreased both D3 mRNA expression and activity. This led to increased intracellular T3 concentrations. The D3 decrease was prevented when NF-κB or AP-1 was inhibited. TRα1 mRNA expression decreased in SK-N-AS cells incubated with LPS, but knockdown of the TRα in SK-N-AS cells did not prevent the LPS-induced D3 decrease. Conclusions: We conclude that the inflammation-induced D3 decrease in the hypothalamus is mediated by the inflammatory pathways NF-κB and AP-1, but not TRα1. Furthermore, the observed decrease modulates intracellular T3 concentrations. Our results suggest a concerted action of inflammatory modulators to regulate both hypothalamic D2 and D3 activities to increase the local TH concentrations.

Maternal photoperiodic programming enlightens the internal regulation of thyroid-hormone deiodinases in tanycytes.

Seasonal rhythms in physiology are widespread among mammals living in temperate zones. These rhythms rely on the external photoperiodic signal being entrained to the seasons, although they persist under constant conditions, revealing their endogenous origin. Internal long-term timing (circannual cycles) can be revealed in the laboratory as photoperiodic history-dependent responses, comprising the ability to respond differently to similar photoperiodic cues based on prior photoperiodic experience. In juveniles, history-dependence relies on the photoperiod transmitted by the mother to the fetus in utero, a phenomenon known as "maternal photoperiodic programming" (MPP). The response to photoperiod in mammals involves the nocturnal pineal hormone melatonin, which regulates a neuroendocrine network including thyrotrophin in the pars tuberalis and deiodinases in tanycytes, resulting in changes in thyroid hormone in the mediobasal hypothalamus. This review addresses MPP and discusses the latest findings on its impact on the thyrotrophin/deiodinase network. Finally, commonalities between MPP and other instances of endogenous seasonal timing are considered, and a unifying scheme is suggested in which timing arises from a long-term communication between the pars tuberalis and the hypothalamus and resultant spontaneous changes in local thyroid hormone status, independently of the pineal melatonin signal.

[Osteoarthropathies and Myopathies associated with Disorders of the Thyroid Endocrine System]. / Osteoarthropathien und Myopathien bei Schilddrüsenerkrankungen.

Triiodothyronine (T3) is a key regulator of bone, muscle and articular cartilage. Musculoskeletal symptoms of hyperthyroidism include loss of bone mass finally leading to osteoporosis and weakness of the skeletal musculature. Hypothyroidism on the other side frequently leads to muscle stiffness and cramping and, occasionally, results in rhabdomyolysis. To prevent terminal differentiation of chondrocytes with consecutive cartilage degeneration, cartilage probably depends on exact regulation of local T3 availability by the intracellular deiodinase system. Recent findings underline the importance of local T3 generation by deiodinase type 2 and support the existence of local hypo- or hyperthyroidism.In the review, the implications of the recent literature for current understanding of osteoarthritis, myopathies and diabetic osteoarthropathy will be discussed. Further emphasis will be placed on the association of autoimmune thyroiditis with musculoskeletal diseases and fibromyalgia.

The Thyroid Hormone Inactivating Type 3 Deiodinase Is Essential for Optimal Neutrophil Function: Observations From Three Species.

Neutrophils are essential effector cells of the innate immune system that have recently been recognized as thyroid hormone (TH) target cells. Cellular TH bioavailability is regulated by the deiodinase enzymes, which can activate or inactivate TH. We have previously shown that the TH inactivating enzyme type 3 deiodinase (D3) is present in neutrophils. Furthermore, D3 knockout (D3KO) mice show impaired bacterial killing upon infection. We hypothesized that D3 plays a role in neutrophil function during infection by actively regulating local TH availability. We measured TH concentrations in cerebrospinal fluid (CSF) from patients with bacterial meningitis and controls. Bacterial meningitis resulted in marked changes in CSF TH levels, characterized by a strong increase of thyroxine and reverse-triiodothyronine concentrations. This altered TH profile was consistent with elevated D3 activity in infiltrating neutrophils at the site of infection. D3 knockdown in zebrafish embryos with pneumococcal meningitis resulted in increased mortality and reduced neutrophil infiltration during infection. Finally, stimulated neutrophils from female D3KO mice exhibited impaired NADPH-oxidase activity, an important component of the neutrophil bacterial killing machinery. These consistent findings across experimental models strongly support a critical role for reduced intracellular TH concentrations in neutrophil function during infection, for which the TH inactivating enzyme D3 appears essential.

Downregulation of Deiodinase 3 is the earliest event in photoperiodic and photorefractory activation of the gonadotropic axis in seasonal hamsters.

In seasonal rodents, reproduction is activated by a long photoperiod. Furthermore, maintaining an inhibitory short photoperiod for over 20 weeks triggers a spontaneous reactivation of the gonadotropic axis called photorefractoriness. Photoactivation is proposed to involve melatonin, hypothalamic thyroid hormones (TH) and (Arg) (Phe)-amide peptides. The mechanisms involved in photorefractoriness are so far unknown. We analyzed the dynamic changes in long photoperiod- and photorefractory-induced activation of reproduction in both Syrian and Djungarian hamsters to validate the current model of photoactivation and to uncover the mechanisms involved in photorefractoriness. We detected a conserved early inhibition of expression of the TH catabolizing enzyme deiodinase 3 (Dio3) in tanycytes, associated with a late decrease of the TH transporter MCT8. This suggests that an early peak of hypothalamic TH may be involved in both photoinduced and photorefractory reactivation. In photoactivation, Dio3 downregulation is followed by an upregulation of Dio2, which is not observed in photorefraction. The upregulation of (Arg) (Phe)-amides occurs several weeks after the initial Dio3 inhibition. In conclusion, we uncovered a so far unreported early inhibition of Dio3. This early downregulation of Dio3 is reinforced by an upregulation of Dio2 in photoactivated hamsters. In photorefractoriness, the Dio3 downregulation might be sufficient to reactivate the gonadotropic axis.

Endocrinology and Pediatric Exercise Science-2016.

The Pediatric Exercise Science Year That Was section aims to highlight the most important (to the author's opinion) manuscripts that were published in 2016 in the field of endocrinology and pediatric exercise science. This year's selection includes studies showing that 1) Induction of T4 to T3 conversion by type 2 deiodinase following aerobic exercise in skeletal muscles was associated with concomitant increase in peroxisome proliferatoractivated receptor-γ coactivator-1α, and mitochondrial oxidative capacity and therefore plays an important mechanistic role in the muscle adaptation to exercise training. 2) Hypothyroidism in fetal and early postnatal life was associated with impaired spatial learning and memory and with reduced hippocampal brain-derived neurotrophic factor in male and female rat pups. Forced (treadmill) and voluntary (wheel) exercise alleviated all these biochemical and neuro-cognitive deficits. 3) The relationship between different exercise intensities and carbohydrate requirements to maintain euglycemia at basal insulin levels among adolescent and young adults with Type 1 diabetes are nonlinear but rather inverted- U with no exogenous glucose required to maintain stable glucose level at high-intensity exercise (80%). The implication of these studies to the pediatric population, their importance and the new research avenues that were opened by these studies is emphasized.

Thyroid Hormone Acts Locally to Increase Neurogenesis, Neuronal Differentiation, and Dendritic Arbor Elaboration in the Tadpole Visual System.

Thyroid hormone (TH) regulates many cellular events underlying perinatal brain development in vertebrates. Whether and how TH regulates brain development when neural circuits are first forming is less clear. Furthermore, although the molecular mechanisms that impose spatiotemporal constraints on TH action in the brain have been described, the effects of local TH signaling are poorly understood. We determined the effects of manipulating TH signaling on development of the optic tectum in stage 46-49 Xenopus laevis tadpoles. Global TH treatment caused large-scale morphological effects in tadpoles, including changes in brain morphology and increased tectal cell proliferation. Either increasing or decreasing endogenous TH signaling in tectum, by combining targeted DIO3 knockdown and methimazole, led to corresponding changes in tectal cell proliferation. Local increases in TH, accomplished by injecting suspensions of tri-iodothyronine (T3) in coconut oil into the midbrain ventricle or into the eye, selectively increased tectal or retinal cell proliferation, respectively. In vivo time-lapse imaging demonstrated that local TH first increased tectal progenitor cell proliferation, expanding the progenitor pool, and subsequently increased neuronal differentiation. Local T3 also dramatically increased dendritic arbor growth in neurons that had already reached a growth plateau. The time-lapse data indicate that the same cells are differentially sensitive to T3 at different time points. Finally, TH increased expression of genes pertaining to proliferation and neuronal differentiation. These experiments indicate that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting cell proliferation and differentiation and by acting on neurons to increase dendritic arbor elaboration. SIGNIFICANCE STATEMENT: Thyroid hormone (TH) is a critical regulator of perinatal brain development in vertebrates. Abnormal TH signaling in early pregnancy is associated with significant cognitive deficits in humans; however, it is difficult to probe the function of TH in early brain development in mammals because of the inaccessibility of the fetal brain in the uterine environment and the challenge of disambiguating maternal versus fetal contributions of TH. The external development of tadpoles allows manipulation and direct observation of the molecular and cellular mechanisms underlying TH's effects on brain development in ways not possible in mammals. We find that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting neural progenitor cell proliferation and differentiation and by acting on neurons to enhance dendritic arbor elaboration.

Intracellular thyroid hormone metabolism as a local regulator of nuclear thyroid hormone receptor-mediated impact on vertebrate development.

BACKGROUND: Thyroid hormones (THs) play an essential role in vertebrate development, acting predominantly via nuclear TH receptors (TRs) which are ligand-dependent transcription factors. Binding of the ligand (predominantly T3) induces a switch from gene activation to gene repression or vice versa. Iodothyronine deiodinases (Ds) and TH transporters are important regulators of intracellular T3 availability and therefore contribute to the control of TR-dependent development. FOCUS: The present review discusses the possible roles of Ds and TH transporters in regulating embryonic and larval (pre-juvenile) TR-dependent development in vertebrates. It focuses mainly on well-known model species for direct and indirect vertebrate development, including zebrafish, Xenopus, chicken and mouse. Data are provided on stage- and tissue/cell-specific changes in expression of Ds and TH transporters. This information is combined with functional data obtained from gain-and-loss of function studies. CONCLUSION: Knockout/knockdown of each type of D has provided strong evidence for their implication in the control of important developmental processes and several D expression patterns and functions have been conserved throughout vertebrate evolution. Knockout/knockdown of the inactivating D3 enzyme indicates that a premature switch from unliganded to liganded TR action is often more detrimental than a delayed one. The majority of ontogenetic studies on TH transporter distribution and function have focused on brain development, showing variable impact of knockout/knockdown depending on the species. Future research in different models using conditional silencing will hopefully further improve our understanding on how TH transporters, Ds and TRs cooperate to regulate TR-mediated impact on vertebrate development. This article is part of a Special Issue entitled: Nuclear receptors in animal development.

Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage.

BACKGROUND: Although osteoarthritis (OA) is the commonest joint disorder and has a rising prevalence as the population ages, no drugs are available that prevent or delay the onset and progression of disease. Recent studies identified the DIO2 gene encoding type 2 deiodinase (D2) as a susceptibility locus for OA, and further data suggest deiodinase-regulated local availability of triiodothyronine (T3) in the joint plays an important role in cartilage maintenance and repair. To investigate the hypothesis that reduced tissue T3 availability protects joints from development of OA, the joint phenotypes of adult mice lacking D2 (D2KO) or lacking both D1 and D2 (D1D2KO), the only enzymes that catalyze conversion of the prohormone thyroxine to active T3, were determined. METHODS: Knee joints were prepared from male 16-week-old adult wild type (WT; n=9), D2KO (n=5), and D1D2KO (n=3) mice. Articular cartilage pathology was scored using the Osteoarthritis Research Society International (OARSI) histopathology scale for murine OA to determine the severity and extent of disease. Digital X-ray microradiography was used to determine the area and mineral content of subchondral bone immediately beneath the articular cartilage surface. RESULTS: There were no differences in maximum and standardized OA scores, cartilage erosion indices, or articular cartilage cellularity among WT, D2KO, and D1D2KO mice. Subchondral bone area did not differ among genotypes, but mineral content was markedly increased in both D2KO and D1D2KO mice compared to WT. CONCLUSIONS: Although adult D2KO mice have normal articular cartilage and no other features of spontaneous joint damage, they exhibit increased subchondral bone mineral content.

[Thyroid hormone and skeletal metabolism].

The role of the hypothalamic-pituitary-thyroid axis is important in normal skeletal development, gain of bone mass, and regulation of adult bone metabolism. Hypothyroidism in childhood causes delayed bone maturation and growth disturbance and thyroid dysfunction in adult induces altered bone remodeling and an increased risk of bone fracture. Thyroid hormone actions in skeletal cells are mainly mediated by thyroid hormone receptor α (TRα) . The responses to thyroid hormone are regulated by type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3) , which convert prohormone (T4) to active hormone (T3) . Euthyroid status is necessary for the homeostasis of human bone metabolism.

Knockdown of type 3 iodothyronine deiodinase severely perturbs both embryonic and early larval development in zebrafish.

Exposure to appropriate levels of thyroid hormones (THs) at the right time is of key importance for normal development in all vertebrates. Type 3 iodothyronine deiodinase (D3) is the prime TH-inactivating enzyme, and its expression is highest in the early stages of vertebrate development, implying that it may be necessary to shield developing tissues from overexposure to THs. We used antisense morpholino knockdown to examine the role of D3 during early development in zebrafish. Zebrafish possess 2 D3 genes, dio3a and dio3b. Here, we show that both genes are expressed during development and both contribute to in vivo D3 activity. However, dio3b mRNA levels in embryos are higher, and the effects of dio3b knockdown on D3 activity and on the resulting phenotype are more severe. D3 knockdown induced an overall delay in development, as determined by measurements of otic vesicle length, eye and ear size, and body length. The time of hatching was also severely delayed in D3-knockdown embryos. Importantly, we also observed a severe disturbance of several aspects of development. Swim bladder development and inflation was aberrant as was the development of liver and intestine. Furthermore, D3-knockdown larvae spent significantly less time moving, and both embryos and larvae exhibited perturbed escape responses, suggesting that D3 knockdown affects muscle development and/or functioning. These data indicate that D3 is essential for normal zebrafish embryonic and early larval development and show the value of morpholino knockdown in this model to further elucidate the specific role of D3 in some aspects of vertebrate development.

Selenium and the thyroid.

PURPOSE OF REVIEW: To provide information on the role of the essential trace element selenium, which enables appropriate thyroid hormone synthesis, secretion, and metabolism, and to discuss supplementation with various selenium compounds, which prevent thyroid diseases such as goiter and exert beneficial effects in thyroid autoimmune diseases. RECENT FINDINGS: Selenium administration in both autoimmune thyroiditis (M. Hashimoto) and mild Graves' disease improves clinical scores and well-being of patients and reduces autoimmune antibody titres in several prospective, placebo-controlled supplementation studies. SUMMARY: Adequate nutritional supply of selenium, together with the two other essential trace elements iodine and iron, is required for a healthy thyroid during development and adolescence, as well as in the adult and aging populations.

Photoperiod history-dependent responses to intermediate day lengths engage hypothalamic iodothyronine deiodinase type III mRNA expression.

Perihypothalamic thyroid hormone signaling features prominently in the seasonal control of reproductive physiology. Triiodothyronine (T(3)) signaling stimulates gonadal development, and decrements in T(3) signaling are associated with gonadal regression. Type 3 iodothyronine deiodinase (DIO3) converts the prohormone thyroxine (T(4)) into biologically inactive 3,3',5'-triiodothyronine, and in long-day breeding Siberian hamsters exposure to long (LD) and short (SD) photoperiods, respectively, inhibit and stimulate hypothalamic dio3 mRNA expression. Reproductive responses to intermediate-duration photoperiods (IntD) occur in a history-dependent manner; IntDs are interpreted as inhibitory only when preceded by longer photoperiods. Because dio3 expression has only been evaluated under LD or SD photoperiods, it is not known whether hypothalamic dio3 encodes absolute photoperiod duration or the reproductive interpretation of photoperiod. Male Siberian hamsters with and without a prior history of LD were exposed to IntD photoperiods, and hypothalamic dio3 mRNA expression was measured 6 wk later. Hamsters with a LD photoperiod history exhibited gonadal regression in IntD and a marked upregulation of hypothalamic dio3 expression, whereas in hamsters without prior exposure to LD, gonadal responses to IntD were absent, and dio3 expression remained low. Patterns of deiodinase expression in hamsters maintained in chronic IntD photoperiods did not appear to reflect feedback effects of gonadal status. Hypothalamic expression of dio3 does not exclusively reflect ambient photoperiod, but rather the context-dependent reproductive interpretation of photoperiod. Neuroendocrine mechanisms that compare current and prior photoperiods, which permit detection of directional changes in day length, occur either upstream, or at the level, of hypothalamic dio3 expression.

The role of type II deiodinase polymorphisms in clinical management of hypothyroid patients treated with levothyroxine.

STUDY OBJECTIVE: Several factors can affect achieving the goals with levothyroxine (L-T4) therapy. This study investigates the clinical and biochemical response to L-T4 replacement therapy in hypothyroid patients in correlation with genetic variation in Deiodinase type || (DIO2) gene. DESIGN AND SETTING: This is a cross-sectional correlation study. The setting was the diabetes and endocrinology clinics at 2 Jordanian Hospitals. METHODOLOGY: Patients with primary hypothyroidism who are controlled on stable L-T4 replacement therapy were recruited and thyroid function test was performed. Genetic analysis to detect 4 single nucleotide polymorphisms (SNPs) rs225011, rs7140952, rs225012 and rs2839858 in DIO2 gene was carried out using the polymerase chain reaction-based restriction fragment length polymorphism assay (PCR-RFLP). RESULTS: There was no correlation between the 4 SNPs in DIO2 gene and replacement doses of L-T4, whereas a statistical significance was found between rs7140952 and central obesity (P<0.05), and systolic and diastolic blood pressure (P<0.05). The dose of L-T4 was associated with lower levels of TSH, fT4, central obesity, body mass index and waist circumference. CONCLUSION: While L-T4 dose is associated with several positive effects on hypothyroid patients, none of the examined SNPs in DIO2 is correlated with replacement doses of the drug. However, rs7140952 polymorphism is associated with components of metabolic syndrome including blood pressure and central obesity.

The deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation.

BACKGROUND: Thyroid hormone influences gene expression in virtually all vertebrates. Its action is initiated by the activation of T4 to T3, an outer ring deiodination reaction that is catalyzed by the type 1 or the type 2 iodothyronine selenodeiodinases (D1 or D2). Inactivation of T4 and T3 occurs via inner ring deiodination catalyzed by the type 3 iodothyronine selenodeiodinases (D3). The T4 concentration is generally quite stable in human plasma, with T3 levels also remaining constant. Deiodinase actions are tightly regulated in both pre- and post-natal life when they are required to make local adjustments of intracellular T3 concentrations in a precise spatio- and temporal manner. Although all the signals governing the dynamic expression of deiodinases in specific cell types are not known, many important regulatory factors have been deciphered. SCOPE OF REVIEW: This review provides striking examples from the recent literature illustrating how the expression of D2 and D3 is finely tuned during maturation of different organs, and how their action play a critical role in different settings to control intracellular T3 availability. MAJOR CONCLUSIONS: Emerging evidence indicates that in various cell contexts, D2 and D3 are expressed in a dynamic balance, in which the expression of one enzyme is coordinately regulated with that of the other to tightly control intracellular T3 levels commensurate with cell requirements at that time. GENERAL SIGNIFICANCE: Deiodinases control TH action in a precise spatio-temporal fashion thereby providing a novel mechanism for the local paracrine and autocrine regulation of TH action. This remarkable tissue-specific regulation of intracellular thyroid status remains hidden due to the maintenance of constant circulating TH concentrations by the hypothalamic-pituitary-thyroid axis. This article is part of a Special Issue entitled Thyroid hormone signalling.