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PubMed1992

The movement of thyroid hormones in the central nervous system.

Thyroid hormones in the central nervous system (CNS) present a number of complexities which include a marked difference in hormone effects on the developing brain compared to the mature brain, extensive regional heterogeneity within the brain, and alternate ways by which the hormones gain entry to the CNS and its cells. Furthermore, most of the T3 found within brain cells is derived from the T4 that they have accumulated. This brief review concerns the movement of the thyroid hormones as they leave the bloodstream and make their way into and through the CNS. There are many sites for potential control of thyroid hormone transport into the central nervous system. The blood brain barrier and the choroid plexus may work in tandem as two parallel resistors subjected to different controls to maintain brain interstitial levels of thyroid hormone at near constant levels. Thyroid hormone may enter neurons directly from the interstitial fluid or indirectly from the glial cells. Nonetheless, both neurons, perhaps at the synaptosome, and glial cells are capable of transporting and concentrating thyroid hormones at physiological levels.

Animals↗

PubMed1991

Differential DNA binding by monomeric, homodimeric, and potentially heteromeric forms of the thyroid hormone receptor.

Binding of the thyroid hormone receptor (TR) to thyroid hormone-responsive elements (TREs) is crucial for regulation of gene expression by thyroid hormone. The TR binds to each half-site of a palindromic TRE separately, as a monomer, or simultaneously, as a homodimer. In addition, the TR monomer interacts with a 42-kDa protein that may be responsible for an increase in the apparent size and stability of the TR-TRE complex after incubation with liver nuclear extract. The multiple DNA-binding forms of the TR contact the TRE differently but compete for binding in a dynamic equilibrium which is highly dependent on the relative concentrations of TR and nuclear protein. Thus, protein-protein interactions are likely to determine the context in which the TR binds to target genes and regulates the transcriptional response to thyroid hormone.

Amino Acid Sequence↗

PubMed2004

[Thyroid hormone resistance syndrome].

Resistance to thyroid hormone (RTH) is a syndrome characterized by elevated serum thyroid hormone (TH) levels and elevated or inappropriately normal thyrotropin levels. In general, patients exhibit TH resistance in the pituitary and peripheral tissues. The phenotype of RTH is variable; the affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation, the variable hyposensitivity to TH among individuals as well as in different tissues. In almost all cases the genetic basis of RTH lies in mutation of the carboxyl-terminus of the ss-thyroid hormone receptor. RTH is a dominant disorder, except in one family; most individuals are heterozygous for the mutant allele. New standard techniques and genetically engineered mouse model systems have increased our understanding on TH receptor action, in particular, how mutant thyroid receptors from RTH patients can block wild-type thyroid receptor function (dominant negative activity), and how the mutant receptors can differently affect various tissues and individuals.

Animals↗

PubMed2000

Thyroid hormones and treatment of obesity.

Thyroid hormones have important thermogenic function. Nevertheless, thyroid dysfunctions are often associated with minor changes in body weight and fat mass. On the other hand, both overfeeding and fasting have important effects on iodothyronine metabolism and regulation of deiodinase activity. Although under debate, there are clinical and theoretical reasons to administer low-dose thyroid hormones (T3) in selected obese patients. This short review deals with both pathophysiological and clinical aspects of thyroid hormone used in the therapy of obesity.

Body Temperature Regulation↗

PubMed2004

[Thyroid hormone metabolism and action].

Reductive deiodination of thyroid hormones at the phenolic and tyrosyl ring leads to the activation or inactivation of the thyromimetic activity inherent to thyroid hormones. Alterations in the activities of the three selenocysteine-containing enzymes, the iodothyronine deiodinases, have been reported during development and in specific cells and tissues of the adult organism. Furthermore, pathophysiological changes in the deiodinase expression lead to therapeutically relevant disturbances of the homeostasis of thyroid hormones. Metabolisation of thyroid hormones by conjugation of their phenolic 4'-OH group, their alanine side chain or cleavage of their diphenylether bridge also contributes to both local and systemic supply of thyromimetic activity or hormone degradation. Further components mediating the pleiotropic action of thyroid hormones in part include redundant T3 receptors, binding and transport proteins, metabolising enzymes and T3-regulated gene products. This is achieved in a finely tuned manner with multiple feedback control, malfunction or complete failure of individual components and networks involved in the iodothyronine metabolism and thyroid hormone action can thus be compensated or prevented.

Feedback↗

PubMed1984

Reduced triiodothyronine content in liver but not pituitary of the uremic rat model: demonstration of changes compatible with thyroid hormone deficiency in liver only.

Intracellular thyroid hormone concentration and action were examined in the liver and the pituitary of a nephrectomized rat model (Nx); the results were compared with those obtained from control (C), thyroidectomized (Tx), and nephrectomized-thyroidectomized (NxTx) littermates. Based on the severity of the uremia, Nx rats were subdivided into Nx1 and Nx2 groups; the former included rats with serum urea nitrogen of less than 100 mg/dl and the latter rats with serum urea nitrogen greater than 100 mg/dl. A group of rats pair-fed to the Nx rats was also included (PF). In the liver, nuclear T3 content (picograms per g liver) and T3-receptor binding capacity (Cmax, picograms T3 per mg DNA) were measured. The respective results from all groups of rats were as follows (asterisks denote values differing from C with a P value less than 0.05): C, 308 +/- (SE) 45 and 121 +/- 11; Nx1, 245 +/- 43 and 85 +/- 15; Nx2, 163 +/- 19 and 74 +/- 7; Tx, 43 +/- 11 and 91 +/- 10; NxTx, 33 +/- 10 and 54 +/- 6; and PF, 237 +/- 20 and 121 +/- 9. T3 receptor binding affinity (Ka), ranging from 3.62-5.28 X 10(9) M-1, was not significantly different among the six groups of rats. In the pituitary, T3 content (picograms per mg pituitary) was reduced only in the Tx rats, being 3.13 +/- 0.89 as compared to 7.04 +/- 1.48 in the C rats (P less than 0.05). In the Nx1, Nx2, and PF rats, pituitary T3 contents were 9.81 +/- 3.22, 13.01 +/- 3.60, and 7.83 +/- 1.08, respectively, and were not different from the C rats. Serum TSH was reciprocally elevated only in the Tx rats. The reduction in hepatic nuclear T3 content and T3-Cmax in the Nx2 rats is consistent with the presence of selective tissue deficiency of thyroid hormone. This is in agreement with the observation of reduced activity of two liver enzymes known to be under thyroid hormone regulation. The pituitary, however, had normal T3 content, suggesting a dissociation in thyroid hormone-dependent metabolic status between a peripheral tissue (liver) and the pituitary. This explains the failure to observe an increase in the serum TSH level, a manifestation of reduced intracellular rather than serum T3 concentration. Decreased food intake appeared not to be the cause of thyroid hormone abnormalities observed in uremia, as PF rats failed to manifest the changes found in Nx rats.

Animals↗

PubMed1989

A domain containing leucine-zipper-like motifs mediate novel in vivo interactions between the thyroid hormone and retinoic acid receptors.

The thyroid hormones and retinoic acid are potent modulators of differentiation, development, and gene expression. The transcriptional activities of these ligands are mediated by closely related nuclear receptors which bind and activate identical hormone responsive DNA elements. We noticed that a region within the ligand binding or E domain is well conserved between receptors for these hormones. This region contains hydrophobic heptad repeats that are structurally similar to the leucine-zipper dimerization domain. To study the function of this conserved domain, we examined the transcriptional responses of thyroid hormone receptor/c-erbA deletion mutants which lacked the heptad repeats. We previously reported that the chick c-erbA-alpha possesses hormone-independent (constitutive) activity in cells which express endogenous rat thyroid hormone receptor. We now demonstrate that this activity is abolished upon deletion of the conserved heptad repeats. This suggests that the heptad repeats mediate in vivo interactions between chick c-erbA and rat thyroid hormone receptors. To further test this hypothesis deletion mutants of chick c-erbA were constructed which contained all eight heptad repeats but which lacked the zinc-finger DNA binding domain. Although these mutants are transcriptionally inactive, they act in a dominant-negative fashion to block trans-activation by both the chick c-erbA-alpha and the endogenous thyroid hormone and retinoic acid receptors. We suggest that the heptad repeats mediate the formation of inactive mutant/wild-type hetero-dimers. Dimer formation suggests a mechanism to account for the dominant-negative phenotypes displayed by nonhormone binding variants of c-erbA, the proto-oncoprotein v-erbA and patients with the generalized thyroid hormone resistance syndrome.

Amino Acid Sequence↗

PubMed2004

Thyroid hormone and the cardiovascular system.

Thyroid hormone is an important regulator of cardiac function and cardiovascular hemodynamics. Triiodothyronine, (T(3)), the physiologically active form of thyroid hormone, binds to nuclear receptor proteins and mediates the expression of several important cardiac genes, inducing transcription of the positively regulated genes including alpha-myosin heavy chain (MHC) and the sarcoplasmic reticulum calcium ATPase. Negatively regulated genes include beta-MHC and phospholamban, which are down regulated in the presence of normal serum levels of thyroid hormone. T(3) mediated effects on the systemic vasculature include relaxation of vascular smooth muscle resulting in decreased arterial resistance and diastolic blood pressure. In hyperthyroidism, cardiac contractility and cardiac output are enhanced and systemic vascular resistance is decreased, while in hypothyroidism, the opposite is true. Patients with subclinical hypothyroidism manifest many of the same cardiovascular changes, but to a lesser degree than that which occurs in overt hypothyroidism. Cardiac disease states are sometimes associated with the low T(3) syndrome. The phenotype of the failing heart resembles that of the hypothyroid heart, both in cardiac physiology and in gene expression. Changes in serum T(3) levels in patients with chronic congestive heart failure are caused by alterations in thyroid hormone metabolism suggesting that patients may benefit from T(3) replacement in this setting.

Blood Vessels↗

PubMed1993

[Structure and function of the thyroid hormone receptor].

Cloning of the thyroid hormone receptor and its identification as a cellular counterpart of the viral oncogene v-erbA was a major breakthrough in the study of thyroid hormone action. However, contrary to our initial expectations, many astonishing findings which have accumulated since the receptor cloning, especially the presence of two receptor types, made the elucidation of the thyroid hormone action extremely complicated. In this paper, we mainly did a phylogenic comparison of the amino acid sequence between alpha- and beta-type receptor from Xenopus laevis to humans, hoping to obtain some clue to clarify the functional differences between these receptors. There are several consistent amino acid differences between alpha- and beta-receptor through species in the DNA binding domain, one of which is non-conservative and is located in the portion supposed to be critical to the protein-protein interaction. We believe that clarification of the physiological significance of the presence of two receptor types will facilitate the study of thyroid hormone action.

Amino Acid Sequence↗

PubMed1997

Thyroid hormone receptors in perennibranchiate amphibians.

Thyroid hormone has long been known to induce metamorphosis in amphibians. The understanding of the molecular steps controlling the completion of metamorphosis has nevertheless been hampered by the complexity of this event. The comparison of organisms in which metamorphosis does or does not occur, may provide clues into the molecular cascade that control it. Up to now the available data suggest that perennibranchiate amphibians retain their larval characters mainly because their tissues do not respond to thyroid hormones. In such a context the recent identification of a thyroid hormone receptor alpha in the perennibranchiate Proteus anguinus is provocative (Ho Huynh et al., Int. J. Dev. Biol. 40:537-543, 1996). In the present paper, we provide evidences that this recently described sequence is in fact a sequence from Xenopus laevis. Indeed, we identified the authentic thyroid hormone receptors of both alpha and beta types in two perennibranchiate species Necturus maculosus and Proteus anguinus. The various controls required to ascertain the authenticity of a developmental gene cloned by PCR or RT-PCR analysis are presented. The results reported in the present paper are relevant with phylogenetical analysis. This induces our team to conclude that the Proteus TR alpha sequence reported by Ho Huynh et al. (1996) reflects a contamination of the RT-PCR by Xenopus laevis material.

Amphibians↗

PubMed1995

The N-terminal region (A/B) of rat thyroid hormone receptors alpha 1, beta 1, but not beta 2 contains a strong thyroid hormone-dependent transactivation function.

In this study we have investigated the role of the N-terminal region of thyroid hormone receptors (TRs) in thyroid hormone (TH)-dependent transactivation of a thymidine kinase promoter containing TH response elements composed either of a direct repeat or an inverted palindrome. Comparison of rat TR beta 1 with TR beta 2 provides an excellent model since they share identical sequences except for their N termini. Our results show that TR beta 2 is an inefficient TH-dependent transcriptional activator. The degree of transactivation corresponds to that observed for the mutant TR delta N beta 1/2, which contains only those sequences common to TR beta 1 and TR beta 2. Thus, TH-dependent activation appears to be associated with two separate domains. The more important region, however, is embedded in the N-terminal domain. Furthermore, the transactivating property of TR alpha 1 was also localized to the N-terminal domain between amino acids 19 and 30. Using a coimmunoprecipitation assay, we show that the differential interaction of the N terminus of TR beta 1 and TR beta 2 with transcription factor IIB correlates with the TR beta 1 activation function. Hence, our results underscore the importance of the N-terminal region of TRs in TH-dependent transactivation and suggest that a transactivating signal is transmitted to the general transcriptional machinery via a direct interaction of the receptor N-terminal region with transcription factor IIB.

3T3 Cells↗

PubMed1995

Influence of thyroid hormones on the regulation of growth hormone secretion.

The effects of thyroid hormones on GH secretion and the mechanisms underlying their action are very similar in man and the laboratory animal. We feel that it is possible to organize the available data into a unique pathophysiological model explaining these complex interactions (Table 1). In summary, physiological levels of circulating thyroid hormones are necessary to maintain normal pituitary GH secretion owing to their direct stimulatory actions. When the serum concentrations of thyroid hormone increase above the normal range there is an increase in hypothalamic somatostatin tone, which in turn suppresses pituitary GH secretion and overrides any stimulatory effects. The suppression of GH secretion by thyroid hormones may be mediated at the hypothalamic level also by a decrease in GHRH release.

Animals↗

PubMed1991

Rat liver c-erb A beta 1 thyroid hormone receptor is a constitutive activator in yeast (Saccharomyces cerevisiae): essential role of domains D,E and F in hormone-independent transcription.

To assess thyroid hormone receptor (TR)-mediated activation of transcription in yeast in the presence or absence of thyroid hormone (T3), we developed a co-expression system using a TR-beta 1 expression vector and a reporter plasmid containing a 16 base pair palindromic thyroid hormone response element (TRE) upstream from a proximal CYC1 promoter that was fused to the beta-galactosidase lac Z gene of Escherichia coli. Although TR-beta 1 functions as a repressor in most mammalian systems, using our system we observed a unique thyroid hormone-independent transcriptional response indicating that wild TR-beta 1 acted as a constitutive activator in yeast; the addition of 1 microM T3 induced a moderate but significant (p less than 0.01) 25-40% further increase in transcriptional activity. Using a series of rat TR-beta 1 mutant constructs, we found that deletion of domain D and portions of E completely eliminated transcriptional activity, whereas truncations of domain F and E permitted a partial (20-40%) response compared to wild TR-beta 1 in the presence or absence of T3. These observations indicate that TR-beta 1 functions as an activator in yeast and that domains D,E and F play important interactive roles in its hormone-independent gene activation with the D domain likely being the most essential. Furthermore, our results suggest that the different transcriptional property of TR-beta 1 in yeast compared to mammalian cells i.e. activator vs repressor function, is likely determined by transcriptional factor differences which are dependent upon cellular origin.

Amino Acid Sequence↗

PubMed2005

Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta.

Thyroid hormone (T(3)) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T(3) receptor beta(PV) (TRbeta(PV)) mice in which a targeted frameshift mutation in TRbeta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRalpha1(PV) mice in which the same PV mutation was targeted to TRalpha1. In contrast to TRbeta(PV) mice, TRalpha1(PV) mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TRalpha1(PV) mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRbeta(PV) mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T(3) action in bone in vivo. The divergent phenotypes observed in TRalpha1(PV) and TRbeta(PV) mice arise because the pituitary gland is a TRbeta-responsive tissue, whereas bone is TRalpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status.

Animals↗

PubMed1981

Familial thyroid hormone resistance.

Eight patients with thyroid hormone resistance were found in four generations of a kindred containing 19 members. Results of studies in this family are consistent with an autosomal dominant mode of inheritance for this disorder. The affected family members were clinically euthyroid but all had goiters and markedly increased serum thyroid hormone levels: thyroxine (T4) = 21.1 +/- 2.1 microgram/dl; triiodothyronine (T3) = 323 +/- 60 ng/dl; free T4 = 5.4 +/- 0.9 ng/dl; and free T3 = 1,134 +/- 356 pg/dl (mean +/- SD). Serum thyrotropin (TSH) levels were normal or slightly elevated in six patients and responded normally to the administration of thyrotropin-releasing hormone (TRH) and L-triiodothyronine. Two patients who had previously undergone subtotal thyroidectomy had elevated baseline serum TSH levels and exaggerated TSH responses to the administration of TRH suggesting subclinical hypothyroidism despite elevated total and free thyroid hormone levels. The absence of thyrotoxicosis and normal serum TSH levels despite elevated serum free T3 and T4 levels in the untreated members of this family are consistent with resistance of pituitary and peripheral tissues to the actions of thyroid hormones. In addition, the absence of hypothyroidism and normal responsiveness of serum TSH to TRH and L-triiodothyronine administration in untreated family members suggest that the thyroid has compensated for the hormone resistance by increased secretory activity under the control of pituitary TSH secretion.

Adolescent↗

PubMed1991

[Immunoregulatory role of thyroid hormone].

The immunoregulatory role of thyroid hormone was investigated in mice weighing 20-30 g. The experimental results showed that the antibody production, transformation of lymphocytes, DTH response (delayed-type hypersensitivity response) and phagocytosis of the peritoneal macrophages were all markedly enhanced when the animals were fed with a daily dose of 2 mg thyroid hormone for 14-18 days. The number of mature T cells in peripheral blood was also increased significantly by the thyroid hormone. When mice were administered with antithyroid drug (methylthiouracil), the antibody production, the transformation of lymphocytes and DTH response were inhibited. Thyroidectomy could also suppress the antibody production. The results suggest that thyroid hormone is involved in the regulation of immune function.

Animals↗

PubMed1996

Serum sex hormone-binding globulin and osteocalcin in systemic nonthyroidal illness associated with low thyroid hormone concentrations.

To test the hypothesis that patients with systemic nonthyroidal illness (NTI) and impaired thyroid hormone metabolism most commonly present with the low T3 or low T4 syndrome are in an euthyroid status at the tissue level, we determined serum sex hormone-binding globulin (SHBG) and osteocalcin (OC) as parameters for thyroid hormone availability to liver and bone. Serum SHBG and OC concentrations were measured in 61 severely ill patients with decreased serum levels of either T3 alone (n = 47) or both T3 and free T4 (n = 14). None of the patients had primary thyroid disorder indicated by regular thyroid sonomorphology and normal basal TSH concentrations. Data were compared with values obtained from age- and sex-matched controls without impairment of thyroid hormone physiology. The respective results from the study groups and from control subjects were as follows: low T3 SHBG, 49 +/- 30 nmol/L; low T4 SHBG, 35 +/- 14 nmol/L; control SHBG, 45 +/- 28 nmol/L; low T3 OC, 0.87 +/- 0.75 nmol/L; low T4 OC, 0.75 +/- 0.71 nmol/L; control OC, 0.98 +/- 0.87 nmol/L. SHBG and OC do not differ significantly between NTI patients with low T3 or low T4 syndrome and controls, and no significant relationship was found between thyroid hormone parameters and SHBG or OC, respectively. We conclude that the term euthyroid sick syndrome applied for the condition of systemic NTI associated with reduced circulating thyroid hormone concentrations appears to be appropriate at the level of hepatocytes and osteoblasts. Data are in partial contradiction to the results of previous studies using alternative serum parameters for assessment of peripheral thyroid hormone action (e.g. angiotensin-converting enzyme). Due to the tissue specificity of the biochemical serum markers, conflicting results may be explained by organ-specific differences in local thyroid hormone exposure. In case of doubt, SHBG and OC determinations may help specify peripheral thyrometabolic status in NTI.

Adult↗

PubMed2004

Thyroid hormone ligands and metabolic diseases.

Thyroid hormones regulate fundamental genes involved in the metabolism, development and homeostasis of vertebrates. The endogenous hormones, L-3, 5, 3'-triiodo-L-thyronine (T(3)) and L-3, 5, 3', 5'-tetraiodo-L-thyronine (T(4)), are of limited use in pharmacological intervention, mainly due to cardiovascular liabilities. There exist two subtypes of thyroid hormone receptors (TR), alpha and beta, unequally distributed in the body. As TRalpha is most abundant in the heart and most effects of thyroid hormones on the heart are mediated through TRalpha, a reasonable strategy is the development of TR agonists that either are tissue selective or that interact selectively with TRbeta. The prospects for the treatment of metabolic diseases with such ligands are considerable and this review describes the massive efforts of the academic and industrial communities during the last decade. It is, however, the author's view that the development of selective ligands only is in its infancy, an opinion highlighted by the limited chemical structural variation of TR ligands as well as the present lack of TR ligands for the treatment of metabolic diseases in clinical phases.

Animals↗