Administration Of Triiodothyronine Research Articles

Triiodothyronine administration reverses vitamin A deficiency-related hypo-expression of retinoic acid and triiodothyronine nuclear receptors and of neurogranin in rat brain.

Recent studies have revealed that retinoids play an important role in the adult central nervous system and cognitive functions. Previous investigations in mice have shown that vitamin A deficiency (VAD) generates a hypo-expression of retinoic acid (RA, the active metabolite of vitamin A) receptors and of neurogranin (RC3, a neuronal protein involved in synaptic plasticity) and a concomitant selective behavioural impairment. Knowing that RC3 is both a triiodothyronine (T3) and a RA target gene, and in consideration of the relationships between the signalling pathways of retinoids and thyroid hormones, the involvement of T3 on RA signalling functionality in VAD was investigated. Thus, the effects of vitamin A depletion and subsequent administration with RA and/or T3 on the expression of RA nuclear receptors (RAR, RXR), T3 nuclear receptor (TR) and on RC3 in the brain were examined. Rats fed a vitamin A-deficient diet for 10 weeks exhibited a decreased expression of RAR, RXR and TR mRNA and of RC3 mRNA and proteins. RA administration to these vitamin A-deficient rats reversed only the RA hypo-signalling in the brain. Interestingly, T3 is able to restore its own brain signalling simultaneously with that of vitamin A and the hypo-expression of RC3. These results obtained in vivo revealed that one of the consequences of VAD is a dysfunction in the thyroid signalling pathway in the brain. This seems of crucial importance since the down regulation of RC3 observed in the depleted rats was corrected only by T3.

Fasting, lipid metabolism, and triiodothyronine in rat gastrocnemius muscle: interrelated roles of uncoupling protein 3, mitochondrial thioesterase, and coenzyme Q.

We investigated the role of uncoupling protein 3 (UCP3) during fasting and examined the effect of triiodothyronine (T3) administration in such a condition. The possible involvement of mitochondrial thioesterase (MTE I) and the role of putative cofactors, such as coenzyme Q (CoQ), was also examined. Here, we report that fasting induced a more than twofold elevation in the expression and activity of MTE I, and an increase in UCP3 expression, without any associated uncoupling activity. Administration of T3 to fasting rats further up-regulated UCP3 as well as MTE I expression, markedly enhanced MTE I enzyme activity and prevented the impairment of the uncoupling activity of UCP3 normally seen during fasting. Indeed, T3-treatment induced an UCP3-dependent decrease in mitochondrial membrane potential, which was abolished by the addition of either GDP or superoxide dismutase (SOD). T3 administration also prevented the marked decrease of CoQ levels observed in fasting rats and this provides evidence that also, in vivo, CoQ represents an essential cofactor for the UCP3-mediated uncoupling. The data also show that MTE I and UCP3 are likely involved in the same biochemical mechanism and that UCP3 postulated functions, such as lipid handling and uncoupling, are not mutually exclusive but may coexist in vivo.

Administration of triiodothyronine and dopamine to broiler chicks increases growth, feed conversion and visceral organ mass

The influences of triiodothyronine (T3) or dopamine (DA) administration on growth, feed conversion, and visceral weights in broiler chicks between the ages of 6 and 12 d posthatch were investigated. In Trial 1, six chicks at age 6 d were randomly administered one of the following treatments: 0.37, 0.74, 1.48, and 2.96 micromol T3/kg BW or 0.07, 0.14, 0.28, and 0.56 micromol DA/kg BW. Both T3 and DA were administered via intraperitoneal injections between the end of sternum and the ends of os pubis, with 0.9% saline as the excepient. In addition, two groups of six birds each were either not injected or injected with excepient only, as controls. Four replications were carried out with a total of 264 chicks. Heart weight as a percentage of feed-deprived body weight (FDBW) of the chicks injected with 2.96 micromol T3/kg BW was heavier than that of controls. Other variables measured were not significantly different between treatments. In trial 2, six chicks at age 6 d were randomly administered, one of the following treatments: 0.56, 1.12, 2.24, and 4.48 micromol T3/kg diet or 0.40, 0.80, 1.60, and 3.20 micromol DA/kg diet as well as a nonsupplemented control. Four replications were carried out with 216 chicks. The results in Trial 2 showed that the effects of T3 (X, micromol/kg diet) on body weight gain (Y1, g) and feed consumption (Y2, g) were linear (Y1 = 310 - 21.5X, R2 = 0.868, P < 0.001 and Y2 = 398 - 22.3X, R2 = 0.765, P < 0.001, respectively). The feed conversion ratio, the weight of liver, the weights of various intestinal segments, the lengths of the duodenum, jejunum and the ileum, as well as weight per centimeter jejunal length, gizzard weight as percentage of FDBW, and the duodenal length per kilogram FDBW all had linear responses (P < 0.05) to the level of dietary supplementation of T3. The effect of dietary supplementation of T3 on the heart weight was quadratic (Y16 = 2.58 + 0.89X - 0.17 X2, R2 = 0.526, P < 0.01). Similarly, the weights of pancreas and gizzard, the heart weight as a percentage of FDBW and the pancreas weight as a percentage of FDBW all had second-order curve responses. Dietary DA supplementation exerted no effect on the variables measured except that the regression of the heart weight as a percentage of FDBW on dietary DA supplementation (X1, micromol/kg diet) existed, namely, Z1 = 0.64 + 0.24 X1 - 0.23 X1(2) + 0.05 X1(3) (R2 = 0.868, P < 0.05).

Thyroid hormone distribution in the mouse brain: the role of transthyretin

Transthyretin is the major thyroxine-binding protein in the plasma of rodents, and the main thyroxine-binding protein in the cerebrospinal fluid of both rodents and humans. The choroid plexus synthesizes transthyretin and secretes it to the cerebrospinal fluid. Although it was suggested that transthyretin might play an important role in mediating thyroxine transfer from the blood into the brain across the choroid plexus–cerebrospinal fluid barrier, newer findings question this hypothesis. Because thyroid hormone passage across brain barriers is a precondition for its action in the CNS, and because brain is an important target of thyroid hormone action, we investigated the role of transthyretin in mediating thyroid hormone access to and distribution within the brain in a transthyretin-null mouse model system. In this report we describe the results derived from use of film autoradiography, a technique that yields definitive morphological results. Film autoradiograms were prepared at 3 and 19 h after intravenous injection of either high specific activity [ 125I]thyroxine or [ 125I]triiodothyronine. Image analyses were designed to demonstrate regional changes in hormone distribution, and to highlight alterations in iodothyronine delivery from ventricles to brain parenchyma. We find no qualitative or quantitative differences in these parameters between the transthyretin-null and the wild-type mouse brain after either [ 125I]thyroxine or [ 125I]triiodothyronine administration. The data presented here now provide definitive evidence that, under standard laboratory conditions, transthyretin is not required for thyroid hormone access to or distribution within the mouse brain. This study also provides the first map of iodothyronine distribution in the brain of the mouse.

Streptozotocin diabetes protects against arrhythmias in rat isolated hearts: role of hypothyroidism

We examined the contribution of hypothyroidism to streptozotocin diabetes-induced alterations in the arrhythmia susceptibility of ex vivo hearts to regional zero-flow ischaemia. Diabetic rats received either protamine zinc insulin (10 IU/kg/day, s.c.) or triiodothyronine (10 μg/kg/day, s.c.) for 8 weeks commencing 72 h after injection of streptozotocin (60 mg/kg, i.p.). Arrhythmias were determined in ex vivo Langendorff-perfused hearts, subjected to a 30-min main left coronary artery occlusion, followed by 30-min reperfusion. Serum free thyroxine concentrations, rectal temperature and ex vivo heart rate were significantly decreased in the 8-week diabetic group ( P<0.001). These changes were prevented by administration of triiodothyronine or insulin. Ventricular fibrillation during reperfusion was abolished in hearts from diabetic rats. This protection was prevented by treatment with either triiodothyronine or insulin. Hearts from methimazole-hypothyroid rats also showed no ventricular fibrillation during reperfusion. The protection against ischaemia–reperfusion–arrhythmias observed in hearts from streptozotocin-diabetic rats may be due to diabetes-induced hypothyroidism.

Hormonal regulation of multiple promoters of the rat mitochondrial glycerol-3-phosphate dehydrogenase gene: identification of a complex hormone-response element in the ubiquitous promoter B.

Rat mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is regulated by multiple promoters in a tissue-specific manner. Here, we demonstrate that thyroid hormone (3,5,3'-tri-iodo-L-thyronine) and steroid hormone but not the peroxisome proliferator clofibrate and retinoic acid stimulate the activation of the ubiquitous promoter B in a receptor-dependent manner, whereas the more tissue-restricted promoters A and C are not inducible by these hormones. Thyroid hormone action is mediated by a direct repeat +4 (DR+4) hormone-response element as identified by deletion and mutation analyses of promoter B in transient transfection analyses. The DR+4 element was able to bind to an in vitro translated thyroid hormone receptor in band-shift and supershift experiments. The hormone-response element comaps with a recognition site for the transcription factor Sp1, suggesting complex regulation of this sequence element. Mutation of this Sp1-recognition site reduces the basal promoter B activity dramatically in HepG2 and HEK293 cells in transient transfection and abolishes the binding of Sp1 in band-shift experiments. As demonstrated by Western-blot experiments, administration of tri-iodothyronine to euthyroid rats increases hepatic mGPDH protein concentrations in vivo. As it has recently been reported that human mGPDH promoter B is not regulated by tri-iodothyronine, this is the first example of a differentially tri-iodothyronine-regulated orthologous gene promoter in man and rat.

Molecular analysis of estrogen induction of preproenkephalin gene expression and its modulation by thyroid hormones

Estrogen receptors (ER) and thyroid hormone receptors (TR) are ligand-dependent nuclear transcription factors. Estrogen-induced preproenkephalin (PPE) gene expression in the hypothalamus is directly related to estrogen-induced lordosis behavior in the rat. In the present study, we showed that the PPE mRNA level in the ventromedial hypothalamus of female rats was significantly decreased by ovariectomy. This decrease was reversed by estrogen replacement in a dose- and time-dependent manner. Using transient transfection and electrophoretic mobility shift assays (EMSA), functional estrogen response elements (ERE) were identified between −437 and −145 base pairs (bp) of the rat PPE gene promoter region. Two ERE-like elements are present between −405 and −364 of the rat PPE gene promoter, which bind ERα as demonstrated by EMSA. Estrogen produced a dose-dependent increase in CAT activity in cotransfection assays with ERα expression vector and a 437PPE-CAT reporter construct containing 437 bp of the rat PPE gene promoter and the CAT reporter gene. This estrogen-induced PPE promoter activity was inhibited by liganded-TR in transient cotransfection assays. Analysis of DNA–protein interactions by EMSA revealed that both ERα and TR (α1 and β1) could bind to the EREs in the rat PPE gene promoter. Furthermore, estrogen induction of PPE mRNA in the ventromedial hypothalamus of the ovariectomized female rat was significantly attenuated by concomitant administration of triiodothyronine. These results suggest that estrogen regulation of the hypothalamic PPE gene expression is mediated through an estrogen-receptor complex directly interacting with the functional EREs in its promoter region; and that this estrogen effect can be modified by thyroid hormones.

Regulation of renal growth and IGFBP-4 expression by triiodothyronine during rat development.

The insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs), which regulate IGF activity, play a fundamental role in renal cell proliferation and differentiation. The thyroid hormone is considered to be required for kidney development; excess induces local hypertrophy and hyperplasia. The aim of the present study was to investigate the possible involvement of the IGF/IGFBP system in thyroid hormone-induced renal growth during the development of the rat. Our results show that thyroid hormone withdrawal by 6-propyl-2-thiouracil (PTU)-treatment of rats at all ages had no effect on renal IGFBP-4 mRNA levels, whereas the abundance of the serum protein was decreased compared to controls. Intraperitoneal triiodothyronine (T3) administration to hypothyroid rats resulted in renal hypertrophy associated with a significant upregulation of IGFBP-4 expression with increased levels of renal IGFBP-4 mRNA and serum protein. T3-induced upregulation of IGFBP-4 expression suggests the involvement of the local IGF/IGFBP system in T3-induced renal hypertrophy.

Thyroid hormones regulate lipid peroxidation and antioxidant enzyme activities in Anabas testudineus (Bloch)

The role of thyroid hormones in metabolic pathways are well known. However, their involvement in lipid peroxidation and antioxidant enzyme activities is not known. In this study, the in vivo injection of 6-propylthiouracil (6-PTU) did not alter the concentration of malondialdehyde (MDA) and conjugated dienes in liver. The administration of triiodothyronine (T 3) or diiodothyronine (T 2) increased the peroxidation rate in hypothyroid fish. However, in normal fish, only a high dose of T 2 caused increased malondialdehyde (MDA) production, rather than T 3. SOD activity was higher in T 2-treated groups in both experiments. Glutathione peroxidase (GPx) activity was also high in hypothyroid fish treated with T 2. In normal specimens, injections of T 3 and T 2 had no effect on GPx activity. Glutathione reductase (GR) activity was not altered by hypothyroidism while T 3 (1 μg) and T 2 (1 μg) increased it. Glutathione content was low in 6-PTU treated fish and high in both T 3- and T 2-treated groups. Thus it can be concluded that not only T 3 but also T 2, formed by sequential monodeiodination of T 4, is also effective in influencing lipid peroxidation and antioxidant enzyme activities in Anabas. Furthermore, hypothyroidism as well as hyperthyroidism affects lipid peroxidation in this teleost.

Spatio-Temporal Expression of TSHβ and FSHβ Genes in Normally Metamorphosing, Metamorphosed, and Metamorphosis-Arrested Hynobius retardatus

Expression patterns of TSHβ and FSHβ genes were investigated in normally metamorphosing and metamorphosed individuals and in goitrogen-treated (TU-SPC), metamorphosis-arrested larvae of a Japanese salamander, Hynobius retardatus, a particular population of which had been reported to show neoteny. Cloned sequences for Hynobius TSHβ and FSHβ covered 66 and 56% of full-length genes, respectively, and both showed relatively high similarity to those of other vertebrates. TSHβ-expressing cells were observed at the ventro-caudal region of the pars distalis of controls, whereas an extraordinarily large number of cells which occupied the whole area of the pituitary glands strongly expressed TSHβ in TU-SPCs. In contrast, no FSHβ-expressing cells were observed in the pituitary glands of controls, whereas several positive cells were observed in the pituitary glands of TU-SPCs. Northern blot analyses revealed a rapid increase of TSHβ expression in the pituitary gland of TU-SPCs that finally reached the level of 20- to 30-fold as much as that of controls. Surprisingly, the expression of FSHβ also increased in the pituitary gland of TU-SPCs compared with that of controls. On the other hand, triiodothyronine administration to the control juveniles reduced the expression of TSHβ compared with saline-administrated controls, suggesting that thyroid hormone (TH) exerts a repressing effect on TSHβ gene. These results suggest that TSHβ overexpression in TU-SPCs must be caused by a deprivation of TH which plays a role in the negative feedback system and that FSHβ expression also might be enhanced by mechanisms similar to those of TSHβ, probably due to certain overlapping of the endocrinological regulation of TSH and FSH in H. retardatus.

Effect of triiodothyronine on reactive oxygen species generation by leukocytes, indices of oxidative damage, and antioxidant reserve

We have examined the effect of short-term triiodothyronine (T3) administration on reactive oxygen species (ROS) generation by leukocytes in 9 euthyroid subjects. At a dose of 60 microg/d orally for 7 days, T3 induced a significant increase in ROS generation by mononuclear cells (MNCs) from 183 +/- 102 mV at baseline to 313 +/- 111 mV on the seventh day (P < .02), and by polymorphonuclear leukocytes (PMNLs) from 195 +/- 94 mV at baseline to 302 +/- 104 mV on the seventh day (P < .02). There was also a significant increase in meta-tyrosine (P < .001) and ortho-tyrosine (P < .001), known indices of oxidative damage to proteins and amino acids. However, there was no increase in plasma thiobarbituric acid-reactive substances (TBARS), an index of oxidative damage to lipids, and in the level of carbonylated proteins, a less sensitive index to assess protein oxidation. There was no decrease in the level of antioxidants such as alpha-tocopherol, vitamin A, beta-carotene, lycopene, and lutein/zeaxanthin. The stimulatory effect on ROS generation may reflect a generalized increase in metabolic activity or may be a specific effect on NADPH oxidase in leukocyte membranes. The absence of a significant change in TBARS, carbonylated proteins, alpha-tocopherol, vitamin A, beta-carotene, lycopene, and lutein/zeaxanthin may reflect the short duration of the increased ROS load.

Acute triiodothyronine administration does not reverse depressed contractile performance following catecholamine exposure in isolated rat cardiomyocytes.

It has been previously suggested that triiodothyronine (T3) may reverse depressed cardiac contractile performance occurring after excessive catecholamine stimulation. We therefore investigated the effects of T3 on intracellular calcium transients and contractile performance in isolated ventricular rat myocytes. Isolated rat myocytes were loaded with the calcium indicator FURA-2/AM (50 micromol/L) and superfused with Krebs-Henseleit solution (pH 7.4). Cells were illuminated by ultraviolet light and fluorescent images obtained with a target camera at 340 nm and 380 nm excitation wavelengths (ratio method). Simultaneous measurements of calcium transients and cell shortening (35 degrees C, electrical field stimulation: 0.5 Hz) were done. At steady state conditions, FURA-2 loaded myocytes were superfused for 60 min with epinephrine (0.1 micromol/L). After 60 min the effect of T3 (10 micromol/L) on calcium transients and shortening were measured. As control, only the effect of 10 micromol/L T3 was analyzed. Epinephrine significantly increased cell shortening and FURA-2 signals to 148.6+/-8.8% and 109.5+/-3.1% (p < 0.01: n = 21; 5 min) respectively. With longer epinephrine exposure, the increase in cell shortening continuously declined to 134.6+/-7.9% with no change in FURA-2 fluorescence. Acute administration of T3 after epinephrine exposure lowered contractile performance from 136.2 +/- 15.5% to 102 +/- 8.2 %, after 10 minutes. In control experiments acute administration of T3 increased basal contractile response from 100% to 115.8+/-3.3% (p<0.01; n = 8; 5 min). This study confirms previous reports of impaired cardiac function after high catecholamine exposure. High catecholamine exposure is associated with a desensitization of contractile proteins for calcium. Acute T3 administration increased contractility in untreated myocytes, but further depressed myocyte shortening in epinephrine-treated cells. Our results show that T3 is ineffective at restoring myocardial contractility after excessive catecholamine stimulation.

Identification of the TRH-like peptides pGlu–Glu–Pro amide and pGlu–Phe–Pro amide in rat thyroid: regulation by thyroid status

Rat thyroid contains thyrotropin-releasing hormone (TRH) and TRH-like peptides which react with TRH antisera. We have identified the TRH-like peptides in the thyroid and examined whether their levels are influenced by thyroid status. The peptides were extracted from the thyroid glands of five hyperthyroid rats and purified by ion-exchange chromatography on SP-Sephadex C25 and reversed-phase high performance liquid chromatography. The principal TRH-immunoreactive component exhibited the same retention on HPLC as synthetic pGlu–Glu–Pro amide and a secondary component corresponded to synthetic pGlu–Phe–Pro amide. In agreement with these assignments the main peptide was shown to be acidic when chromatographed on DEAE-Sephadex A25 and the second peptide neutral. The levels of TRH and TRH-like peptides in the thyroid were investigated in hyper-, hypo- and euthyroid rats. Hyperthyroidism was induced by chronic subcutaneous administration of triiodothyronine (T3) and hypothyroidism was produced by addition of propylthiouracil (PTU) to the drinking water. The amounts of the peptides were determined by radioimmunoassay with a TRH-antiserum, carried out after extraction from the tissues and purification by ion exchange chromatography. The mean concentration of TRH-like peptides in the thyroids of the hyperthyroid rats was 95.5±25.5 pmol/g, the mean concentration in the hypothyroid rats was 11.7±3.4 pmol/g, and in the euthyroid rats 17.6±3.2 pmol/g. The concentrations of TRH were less influenced by thyroid status: the values in hyper-, hypo- and euthyroid rats were 47.5±9.4, 42.1±6.3, and 17.2±1.6 pmol/g respectively. The results show that the levels of the TRH-like peptides in rat thyroid are highly sensitive to thyroid status, suggesting a possible involvement in thyroid regulation.

Acute and early effects of triiodothyronine administration on serum markers of bone and mineral metabolism.

There have been few studies on acute changes of bone metabolism in humans by thyroid hormone. This study aimed to examine the effects of triiodothyronine on serum markers of bone and mineral metabolism during a 7-d course of daily 75 microg therapy in 14 normal volunteers by drawing blood on 1, 2, 3, 5, and 7 d of therapy. Serum calcium concentrations did not significantly change during the course of therapy, while serum phosphorus concentrations were significantly (p < 0.05) decreased from 3.21 +/- 0.43 mg/dL (mean +/- SD) to 2.85 +/- 0.46 mg/dL on the 7th d. Serum PTH concentrations were significantly decreased from 339 +/- 116 pg/mL to 316 +/- 29 pg/mL. Serum concentrations of alkali-phosphatase and bone-specific alkali-phosphatase were not significantly changed, but serum osteocalcin concentrations were significantly increased from 5.71 +/- 1.98 mg/dL to 6.73 +/- 2.24 mg/dL. Serum carboxy-terminal propeptide of type I collagen concentrations were significantly decreased from 137.8 +/- 33.7 microg/L to 119.2 +/- 33.6 microg/L. Serum pyridinoline cross-linked telopeptide domain of type I collagen concentrations, a bone resorption marker, were significantly increased from 3.40 +/- 0.77 to 3.87 +/- 1.05 microg/L, and such significant increase was obtained from the 3rd day. The results indicate that some of bone and mineral markers change rapidly in response to triiodothyronine-induced acute thyrotoxicosis, but the manner of change is not the same as that of chronic thyrotoxicosis.

Effect of triiodothyronine administration on reduced expression of type 1 iodothyronine deiodinase messenger ribonucleic acid in streptozotocin-induced diabetic rats.

To examine the mechanism behind a decrease in type 1 iodothyronine deiodinase (D1) gene expression in diabetes mellitus, we evaluated the effect of administering T3 and/or insulin on D1 activity and the mRNA levels in the liver of streptozotocin (STZ)-induced diabetic rats. STZ (100 mg/kg BW) was administered to male Wistar rats, and the rats were divided into four groups as follows: (1) STZ alone, (2) STZ and T3 (5 microg/100 g BW daily for 7 days), (3) STZ and insulin (intermediate-acting insulin, 4 units/100 g BW daily for 7 days), and (4) STZ, T3, and insulin. Blood glucose levels increased in Group 1, but were normalized in Group 3. Serum T3 levels were markedly decreased in Group 1. They were within normal limits 24 hours after the last administration of T3 in Group 2 and after the administration of insulin in Group 3. T3 levels were supranormal in Group 4. TSH levels were normal in Groups 1 and 3, but were suppressed in Groups 2 and 4, suggesting that rats in Groups 2 and 4 were actually in a hyperthyroid state after injecting a large amount of T3. D1 activity in Group 1 was reduced significantly, but it was normal in Groups 2 and 3, and increased in Group 4. D1 mRNA levels in the liver in Group 1 decreased significantly, but they were increased to within normal limits by adding insulin in Group 3. They were also normal in Group 2 where hyperglycemia was evident and rats were hyperthyroid after administering T3. D1 mRNA in Group 4 increased significantly where glucose levels were normal and T3 levels were increased. We suggest that the decrease in hepatic D1 mRNA in STZ-induced diabetic rats is due to metabolic derangement caused by insulin deficiency in addition to a possible decrease in tissue T3 availability.

Effect of Triiodothyronine Administration on the Recovery of Liver Oxidative Capacity after Partial Hepatectomy

The aim of the present work was to investigate the role of triiodothyronine on liver regeneration after partial hepatectomy in the rat. During the first 3 days of liver regeneration, total protein, total DNA content and total cytochrome c oxidase activity of the residual tissue increased from 30% immediately after partial hepatectomy to 70% of the preoperative values in control rats. In triiodothyronine-treated rats, the increase in total protein was the same (70%), however, the increase in total liver DNA content and total cytochrome c oxidase acitivity was 100 and 135%, respectively during the first 3 days of regeneration. Triiodothyronine administration also increased significantly the activity of mitochondrial ATPase in regenerating liver.

Effect of tri-iodothyronine on leptin release and leptin mRNA accumulation in rat adipose tissue.

Leptin, the product of the obese gene, is produced by white adipocytes. The release of leptin, as well as leptin mRNA content, was enhanced in adipocytes isolated from hypothyroid rats. The administration of tri-iodothyronine (T3) 8 h before death inhibited leptin release by adipocytes incubated for 6 or 24 h. Direct addition of T3 to pieces of adipose tissue enhanced the loss of leptin mRNA seen over 24 h in the presence of dexamethasone plus the beta3-adrenergic agonist Cl 316,243. In contrast, if pieces of adipose tissue were incubated with dexamethasone plus insulin, enhanced the T3 accumulation of leptin mRNA. These results indicate that T3 enhances net adipocyte leptin mRNA accumulation in a condition that approximates the fed state (presence of insulin) but inhibits leptin mRNA accumulation in a condition that approximates the fasted state (absence of insulin).

Safety and Hemodynamic Effects of Intravenous Triiodothyronine in Advanced Congestive Heart Failure

Most patients with advanced congestive heart failure have altered thyroid hormone metabolism. A low triiodothyronine level is associated with impaired hemodynamics and is an independent predictor of poor survival. This study sought to evaluate safety and hemodynamic effects of short-term intravenous administration of triiodothyronine in patients with advanced heart failure. An intravenous bolus dose of triiodothyronine, with or without a 6- to 12-hour infusion (cumulative dose 0.15 to 2.7 μg/kg), was administered to 23 patients with advanced heart failure (mean left ventricular ejection fraction 0.22 ± 0.01). Cardiac rhythm and hemodynamic status were monitored for 12 hours, and basal metabolic rate by indirect calorimetry, echocardiographic parameters of systolic function and valvular regurgitation, thyroid hormone, and catecholamine levels were measured at baseline and at 4 to 6 hours. Triiodothyronine was well tolerated without episodes of ischemia or clinical arrhythmia. There was no significant change in heart rate or metabolic rate and there was minimal increase in core temperature. Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect. Acute intravenous administration of triiodothyronine is well tolerated in patients with advanced heart failure, establishing the basis for further investigation into the safety and potential hemodynamic benefits of longer infusions, combined infusion with inotropic agents, oral triiodothyronine replacement therapy, and new triiodothyronine analogs.

Triiodothyronine (T3) Administration in Patients with Sepsis Induced Euthyroid Sick Syndrome: Hemodynamic and Metabolic Effects

Triiodothyronine (T3) Administration in Patients with Sepsis Induced Euthyroid Sick Syndrome: Hemodynamic and Metabolic Effects

Transcriptional induction of RC3/neurogranin by thyroid hormone: differential neuronal sensitivity is not correlated with thyroid hormone receptor distribution in the brain

RC3/neurogranin is a calmodulin-binding protein kinase C substrate, located in dendritic spines of forebrain neurons. It has been implicated in post-synaptic signal transduction events involving Ca 2+ and calmodulin leading to many forms of synaptic plasticity. RC3 gene expression is under developmental and physiological regulation. The main physiological regulator appears to be thyroid gland activity. Hypothyroidism decreased RC3 mRNA concentration in the brain of post-natal day 22 rats. The affected areas included layer 6 of cerebral cortex, layers 2–3 of retrosplenial cortex, dentate gyrus and the caudate whereas others were not affected by hypothyroidism, such as upper layers of cerebral cortex, the pyramidal layer of the hippocampus and the amygdala. A single administration of triiodothyronine (T3) induced a significant transcriptional increase of RC3 mRNA in hypothyroid rats, 24 h after administration. Differential sensitivity to thyroid hormone was not related to differential expression of T3 receptor isoforms or the T3 receptor inhibitory variant α2. Therefore, it is likely that cell sensitivity to thyroid hormone in the brain depends on T3 receptor-associated factors.