T3 Administration Research Articles

Effects of purslane (<i>Portulaca oleracea</i> L.) powder on growth performance, blood indices, and antioxidant status in broiler chickens with triiodothyronine-induced ascites

Abstract. This study was carried out to evaluate the effects of dietary supplementation of purslane powder (PP) on performance, blood indices, and antioxidant status in broilers with triiodothyronine (T3)-induced ascites. In total, 240 one-day-old male broiler chicks (Ross 308) were randomly assigned to four treatments, with four replicates per treatment and 15 birds per replicate. The experimental diets included (i) a control diet, (ii) a control diet plus 1.5 mg kg−1 of T3 (T3 diet), (iii) a T3 diet with the addition of 1.5 g kg−1 of PP, and (iv) a T3 diet with the addition of 3 g kg−1 of PP. Feed intake and body weight were measured at 10, 24, 39, and 49 days of experiment. Blood and liver samples were collected from two birds in each replicate at 24 and 49 days of experiment. The T3-treated birds had higher (P < 0. 05) right ventricle to total ventricle (RV ∕ TV) ratio and mortality due to ascites compared with the control. In addition, during the entire experimental period (0 to 49 days of experiment) the T3-treated birds had lower (P < 0. 05) feed intake, body weight gain, and production efficiency index and higher (P < 0. 05) feed conversion ratio compared with the control. Dietary supplementation of PP reduced (P < 0. 05) mortality due to ascites and RV ∕ TV ratio, while the production efficiency index was increased (P < 0. 05) by the addition of PP to the diet. The T3-treated birds had higher (P < 0. 05) red blood cell counts, hematocrit percentage, and hemoglobin concentration compared with the control at 24 and 49 days of experiment. Dietary supplementation of PP substantially alleviated (P < 0. 05) the negative effects of T3 on hematocrit and hemoglobin values at both 24 and 49 days of experiment and on red blood cells counts at 49 days of experiment. The T3 birds showed an increase (P < 0. 05) in activities of lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase at 49 days of experiment. However, the detrimental effect of T3 on alanine aminotransferase activity was attenuated (P < 0. 05) by dietary supplementation of PP. The plasma and liver activities of superoxide dismutase, catalase, and glutathione peroxidase were lower (P < 0. 05) in T3-treated birds compared with the control at 24 and 49 days of experiment, whereas malondialdehyde concentrations were elevated (P < 0. 05) by dietary T3 administration. Dietary supplementation of PP, especially at 3 g kg−1, increased (P < 0. 05) the plasma and liver activities of antioxidant enzymes, and reduced (P < 0. 05) the plasma and liver concentrations of malondialdehyde near to the control levels. It is concluded that the supplementation of 3 g kg−1 of PP in diet improves oxidative status and reduces ascites incidence in broiler chickens without impairing their growth performance.

Both 3,5-Diiodo-L-Thyronine and 3,5,3'-Triiodo-L-Thyronine Prevent Short-term Hepatic Lipid Accumulation via Distinct Mechanisms in Rats Being Fed a High-Fat Diet.

3,3′,5-triiodo-L-thyronine (T3) improves hepatic lipid accumulation by increasing lipid catabolism but it also increases lipogenesis, which at first glance appears contradictory. Recent studies have shown that 3,5-diiodothyronine (T2), a natural thyroid hormone derivative, also has the capacity to stimulate hepatic lipid catabolism, however, little is known about its possible effects on lipogenic gene expression. Because genes classically involved in hepatic lipogenesis such as SPOT14, acetyl-CoA-carboxylase (ACC), and fatty acid synthase (FAS) contain thyroid hormone response elements (TREs), we studied their transcriptional regulation, focusing on TRE-mediated effects of T3 compared to T2 in rats receiving high-fat diet (HFD) for 1 week. HFD rats showed a marked lipid accumulation in the liver, which was significantly reduced upon simultaneous administration of either T3 or T2 with the diet. When administered to HFD rats, T2, in contrast with T3, markedly downregulated the expression of the above-mentioned genes. T2 downregulated expression of the transcription factors carbohydrate-response element-binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) involved in activation of transcription of these genes, which explains the suppressed expression of their target genes involved in lipogenesis. T3, however, did not repress expression of the TRE-containing ChREBP gene but repressed SREBP-1c expression. Despite suppression of SREBP-1c expression by T3 (which can be explained by the presence of nTRE in its promoter), the target genes were not suppressed, but normalized to HFD reference levels or even upregulated (ACC), partly due to the presence of TREs on the promoters of these genes and partly to the lack of suppression of ChREBP. Thus, T2 and T3 probably act by different molecular mechanisms to achieve inhibition of hepatic lipid accumulation.

Thyroid Hormone-Induced Expression of the Hepatic Scaffold Proteins Sestrin2, β-Klotho, and FRS2α in Relation to FGF21-AMPK Signaling.

Thyroid hormone (3,3',5-triiodothyronine, T3) accelerates energy metabolism in the liver through mechanisms involving upregulation of AMP-activated protein kinase (AMPK). This study aims to assess the influence of T3 on the expression of the scaffold proteins β-Klotho, fibroblast growth factor receptor substrate 2α (FRS2α), and Sestrin2 in relation to FGF21-AMPK signaling. Male Sprague-Dawley rats were given 0.1 mg T3/kg or hormone vehicle (controls) and studies were done 24 h after treatment. These include measurements of the mRNA expression (qPCR) of hepatic β-Klotho, FGF21, FGF21 receptor-1 (FGFR1), extracellular-signal-regulated kinase 1/2 (ERK1/2), FRS2α, ribosomal S6 kinase-1 (RSK1), liver kinase B1 (LKB1), AMPK, and Sestrin2. Also, protein levels of FGF21, FGFR1 (ELISA), and ERK1/2 (Western blot) were measured. T3 elicited a calorigenic response with higher hepatic mRNA expression of β-Klotho, FRS2α, and FGF21, increased serum FGF21, without changes in liver FGFR1 mRNA and its plasma levels. In addition, T3 enhanced ERK1/2 phosphorylation and the mRNA expression of ERK1/2, RSK1, LKB1, AMPK, and Sestrin2. T3 administration enhances liver FGF21-AMPK signaling involving upregulation of the scaffold proteins β-Klotho, FRS2α, and Sestrin2. β-Klotho and FRS2 induction favours the operation of the FGF21-FGFR1-β-Klotho complex as evidenced by the enhancement in ERK1/2 phosphorylation, whereas that of Sestrin2 recruits LKB1 to achieved AMPK activation, thus supporting a higher energy expenditure condition that may be desirable in some metabolic disorders.

Effects of hyper- and hypothyroidism on the development and proliferation of testicular cells in prepubertal rats.

Thyroid hormones are important in the development and regulation of testes. This study was conducted to determine the effects of hyper- and hypothyroidism on testicular development in prepubertal rats aged 20-70days. Weaning male rats (20days old) until day 70 age were randomly divided into four groups: control, hyperthyroid (hyper-T), hypothyroid (hypo-T) and hypothyroid treated with thyroxine (T4) (hypo-T+T4). The results indicated that thyroid hormones caused a significant effect in body and testis weights, and food and water consumption. In addition there were changes in serum concentrations of tri-iodothyronine, T4, thyroid stimulating hormone (TSH) and testosterone. Histomorphology showed a significant decrease in seminiferous tubule diameter in hyper-T compared to the other groups. Leydig cell numbers showed a significant elevation in hyper-T but not in hypo-T groups. Immunostaining indicated that TSH receptor (TSHR), thyroid hormone receptors α/β (TRαβ) and proliferating cell nuclear antigen (PCNA) have the roles in testicular development. Our findings suggest that hyper- and hypo-thyroidism regulate testicular cell proliferation and spermatogenesis in prepubertal rats, indicating that expression of TSHR, TRαβ and PCNA may be regulated by thyroid hormones that are involved in testicular development; and that the administration of T4 to the hypo-T+T4 group leads to an improvement in the testicular condition.

Hippocampus-dependent memory and allele-specific gene expression in adult offspring of alcohol-consuming dams after neonatal treatment with thyroxin or metformin

Fetal alcohol spectrum disorder (FASD), the result of fetal alcohol exposure (FAE), affects 2–11% of children worldwide, with no effective treatments. Hippocampus-based learning and memory deficits are key symptoms of FASD. Our previous studies show hypothyroxinemia and hyperglycemia of the alcohol-consuming pregnant rat, which likely affects fetal neurodevelopment. We administered vehicle, thyroxine (T4) or metformin to neonatal rats post FAE and rats were tested in the hippocampus-dependent contextual fear-conditioning paradigm in adulthood. Both T4 and metformin alleviated contextual fear memory deficit induced by FAE, and reversed the hippocampal expression changes in the thyroid hormone-inactivating enzyme, deiodinase-III (Dio3) and insulin-like growth factor 2 (Igf2), genes that are known to modulate memory processes. Neonatal T4 restored maternal allelic expressions of the imprinted Dio3 and Igf2 in the adult male hippocampus, while metformin restored FAE-caused changes in Igf2 expression only. The decreased hippocampal expression of DNA methyltransferase 1 (Dnmt1) that maintains the imprinting of Dio3 and Igf2 during development was normalized by both treatments. Administering Dnmt1 inhibitor to control neonates resulted in FAE-like deficits in fear memory and hippocampal allele-specific expression of Igf2, which were reversed by metformin. We propose that neonatal administration of T4 and metformin post FAE affect memory via elevating Dnmt1 and consequently normalizing hippocampal Dio3 and Igf2 expressions in the adult offspring. The present results indicate that T4 and metformin, administered during the neonatal period that is equivalent to the third trimester of human pregnancy, are potential treatments for FASD and conceivably for other neurodevelopmental disorders with cognitive deficits.

Effect of thyroid hormone on cardiac function following orthotopic heart transplantation in piglets

Studies in adult HT have demonstrated improved cardiac function in the recipient following administration of T3 to the donor. The purpose of this experiment was to assess the effects of T3 on the function of the immature donor heart following HT in a piglet model. A total of 32 piglets were divided into 16 donors and 16 recipients. Following creation of brain death, half of the donor piglets were randomized to receive three doses of T3 (0.2μg/kg) along with hydrocortisone (1mg/kg). The donor hearts were then transplanted into the recipient piglets on CPB. Duration of survival off CPB, inotrope score, and EF of heart following CPB were evaluated. There were no differences between the two groups in age, weight, pre-brain death EF, T3 levels, and CPB times. Post-CPB survival times were inversely related to the ischemic times in both groups (Pearson r=-0.80, P<.001), and this relationship was not influenced by T3. There was no difference in inotrope score, EF, or biochemical assessment between the two groups. Administration of T3 in combination with hydrocortisone to the brain-dead donor confers no beneficial effect on myocardial function or survival following HT in a piglet model.

6,7,3′,4′-Tetrahydroxyisoflavone improves the survival of whole-body-irradiated mice via restoration of hematopoietic function

Purpose: 6,7,3′,4′-tetrahydroxyisoflavone (T3) is a novel chemically synthesized compound reported in our previous study. This study was designed to explore the radioprotective effect of T3, and if so, its potential mechanisms.Materials and methods: KunMing mice were exposed to various doses of γ irradiation (60 Co) after being treated with dimethyl sulfoxide (DMSO) or T3. Briefly, survival rate, dose reducing factor (DRF), body weight change (%), spleen index (SI) and thymus index (TI) of irradiated mice with or without different doses of T3 treatment were evaluated routinely. The hematopoietic function of bone marrow was emphatically investigated. In vitro experiments were performed to observe the protective effect of T3 on irradiated human lymphocyte AHH-1 cells by cell viability or flow cytometry (FCM) assays.Results: A single dose of subcutaneous administration of T3 significantly improved the survival rate, and enhanced the restoration of hematopoietic function in irradiated mice. T3 also decreased the apoptosis of irradiated AHH-1 cells in vitro.Conclusions: T3 protected mice against lethal γ irradiation-induced injury probably through the restoration of hematopoietic function. This implied that T3 could be further developed as a radioprotector.

Thyroid states regulate subcellular glucose phosphorylation activity in male mice.

The thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), are very important in organism metabolism and regulate glucose utilization. Hexokinase (HK) is responsible for the first step of glycolysis, catalyzing the conversion of glucose to glucose 6-phosphate. HK has been found in different cellular compartments, and new functions have been attributed to this enzyme. The effects of hyperthyroidism on subcellular glucose phosphorylation in mouse tissues were examined. Tissues were removed, subcellular fractions were isolated from eu- and hyperthyroid (T3, 0.25 µg/g, i.p. during 21 days) mice and HK activity was assayed. Glucose phosphorylation was increased in the particulate fraction in soleus (312.4% ± 67.1, n = 10), gastrocnemius (369.2% ± 112.4, n = 10) and heart (142.2% ± 13.6, n = 10) muscle in the hyperthyroid group compared to the control group. Hexokinase activity was not affected in brain or liver. No relevant changes were observed in HK activity in the soluble fraction for all tissues investigated. Acute T3 administration (single dose of T3, 1.25 µg/g, i.p.) did not modulate HK activity. Interestingly, HK mRNA levels remained unchanged and HK bound to mitochondria was increased by T3 treatment, suggesting a posttranscriptional mechanism. Analysis of the AKT pathway showed a 2.5-fold increase in AKT and GSK3B phosphorylation in the gastrocnemius muscle in the hyperthyroid group compared to the euthyroid group. Taken together, we show for the first time that THs modulate HK activity specifically in particulate fractions and that this action seems to be under the control of the AKT and GSK3B pathways.

Local delivery of thyroid hormone enhances oligodendrogenesis and myelination after spinal cord injury

Objective. Traumatic spinal cord injury (SCI) causes apoptosis of myelin-forming oligodendrocytes (OLs) and demyelination of surviving axons, resulting in conduction failure. Remyelination of surviving denuded axons provides a promising therapeutic target for spinal cord repair. While cell transplantation has demonstrated efficacy in promoting remyelination and functional recovery, the lack of ideal cell sources presents a major obstacle to clinical application. The adult spinal cord contains oligodendrocyte precursor cells and multipotent neural stem/progenitor cells that have the capacity to differentiate into mature, myelinating OLs. However, endogenous oligodendrogenesis and remyelination processes are limited by the upregulation of remyelination-inhibitory molecules in the post-injury microenvironment. Multiple growth factors/molecules have been shown to promote OL differentiation and myelination. Approach. In this study we screened these therapeutics and found that 3, 3′, 5-triiodothyronine (T3) is the most effective in promoting oligodendrogenesis and OL maturation in vitro. However, systemic administration of T3 to achieve therapeutic doses in the injured spinal cord is likely to induce hyperthyroidism, resulting in serious side effects. Main results. In this study we developed a novel hydrogel-based drug delivery system for local delivery of T3 to the injury site without eliciting systemic toxicity. Significance. Using a clinically relevant cervical contusion injury model, we demonstrate that local delivery of T3 at doses comparable to safe human doses promoted new mature OL formation and myelination after SCI.

Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats.

The aim of the present study was to observe the effects of the concurrent administration of thyroxine (T4) and an acetylcholinesterase (AChE) inhibitor, donepezil (DON), on the hypothyroidism-induced ultrastructural changes of the prefrontal cortex (PFC) in adult rats. The acetylcholine (ACh) content and AChE activity was assessed, as well as the expressions of synaptotagmin-1 (syt-1) and SNAP-25 were analyzed in the rats. Adding 0.05% propylthiouracil to rats' drinking water induced a hypothyroid rat model. The animals were treated with T4 and DON administered separately or in combination from the fifth week. Transmission electron microscope analysis revealed that hypothyroidism induced marked ultrastructural changes, including the neurons, the synapses and the myelin sheath in the PFC. T4 or DON treatment improved the morphologic features of the PFC, and the performance of the T4 combined DON group was the closest to the control group. Moreover, hypothyroidism significantly decreased the content of ACh (29.8%) and activity of AChE (27.8%), which were restored to control values by T4 administration. In addition, DON treatment restored ACh content to normal. At the protein level, hypothyroidism increased the levels of syt-1 and SNAP-25 in the PFC, both of which were not restored to control values following T4 administration, while concurrent administration of T4 and DON was able to induce this effect. These results suggested that adult-onset hypothyroidism induce morphological, biochemical and molecular alterations in the PFC, combined administration of T4 and DON induce plastic changes in the PFC, different from that of the standard T4 therapy, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

Peripheral and central administration of T3 improved the histological changes, memory and the dentate gyrus electrophysiological activity in an animal model of Alzheimer's disease.

The amyloid beta (Aβ) induced Alzheimer's disease (AD) is associated with formation the amyloid plaques, cognitive impairments and decline in spontaneous discharge of neurons. In the current study, we evaluated the effect of subcutaneous (S. C) and intrahippocampal (I. H) administrations of triiodothyronine (T3) on the histological changes, memory and the dentate gyrus (DG) electrophysiological activity in an animal model of AD. Eighty adult male Wistar rats (250-300g) were divided randomly into five groups: Sham-Operated (Sh-O), AD+Vehicle (S. C), AD+Vehicle (I. H), AD+ T3 (S. C) and AD+T3 (I. H). In order to induce animal model of AD, Aβ (10ng/μl, bilaterally) were injected intrahippocampally. Rats were treated with T3 and/or normal saline for 10days. Passive avoidance and spatial memory were evaluated in shuttle box apparatus and Morris water maze, respectively. Neuronal single unit recording was assessed from hippocampal DG. The percent of total time that animals spent in target quarter, the mean latency time (sec), the step through latency and the average number of spikes/bin were decreased significantly in AD rats compared with the Sh-O group (p<0.001) and were increased significantly in AD groups that have received T3 (S. C and I. H) in compared with AD group (p<0.01, p<0.001). Also, formation of amyloid plaques was decreased in AD rats treated with T3.The results showed that T3 injection (S. C and I. H), by reduction of neural damage and increment of neuronal spontaneous activity improved the memory deficits in Aβ-induced AD rats.

Thyroid hormone suppresses ischemia-reperfusion-induced liver NLRP3 inflammasome activation: Role of AMP-activated protein kinase

Thyroid hormone (T3) induces liver preconditioning (PC) against ischemia-reperfusion (IR), a response energetically supported by AMP-activated protein kinase (AMPK) upregulation. The aim of this work is to evaluate the influence of T3 on IR-induced liver NLRP3 inflammasome activation and the relevance of AMPK activity on liver injury by the use of the AMPK inhibitor compound C (CC). Male Sprague-Dawley rats were given 0.1mgT3/kg (time zero) and 10mg CC/kg (time zero and 24h) or the respective vehicles, and subjected to 1h ischemia–20h reperfusion 48h after hormone treatment. Measurements included parameters of liver injury, hepatic levels of mRNAs (qPCR) and proteins (Western Blot or ELISA). IR induced substantial distortion of liver architecture, hepatocyte necrosis, and neutrophil infiltration with increased serum aspartate aminotransferase (AST) levels. T3 suppressed IR liver injury and AST enhancement, effects that were reverted by CC. Concomitantly, IR-induced liver mRNA and protein expression of NLRP3 and interleukin-1β (IL-1β) were restrained by T3, whereas CC eliminated T3-dependent PC. In conclusion, in vivo T3 administration triggers liver PC against IR injury by suppressing the inflammatory response associated with hepatic NLRP3 and IL-1β upregulation, with AMPK playing a causal role regulating energy dynamics to upkeep PC.

Hypothalamic effects of thyroid hormone

Thyroid hormone (TH) is a key driver of metabolism in mammals. Plasma concentrations of TH are kept within a narrow range by negative feedback regulation in the hypothalamus-pituitary-thyroid (HPT) axis. Plasma TH concentrations are an important determinant of metabolic processes in liver and brown adipose tissue (BAT). In addition to endocrine effects of TH derived from the circulation, recent studies have demonstrated additional neural routes for intrahypothalamic thyroid hormone to regulate metabolism in liver and BAT via the sympathetic and parasympathetic branch of the autonomic nervous system (ANS). This review provides an overview of studies reporting metabolic effects of selective administration of T3 within hypothalamic nuclei including the paraventricular nucleus (PVN), the ventromedial nucleus (VMH), the arcuate nucleus (Arc), and the anterior hypothalamic area (AHA).This overview of the literature suggests that intrahypothalamic T3 can have profound effects on hepatic glucose production and insulin sensitivity, energy expenditure in BAT, cardiovascular function and feeding behavior. As the experiments have been performed in experimental animals exclusively, and the timing and route of T3 administration may be an important determinant of effect size, the clinical relevance of these metabolic effects in the chronic setting remains to be established.

EVALUATION OF SERUM IRISIN AND CREATINE KINASE LEVELS IN HYPO- AND HYPERTHYROID RATS

Background: Thyroid dysfunction is one of the most common metabolic disorders that has not been dependent yet in its diagnosis on evaluation of serum levels of thyroid stimulating hormone (TSH), tri-iodothyronine (T3), thyroxine (T4). Other markers like serum irisin which is an adipo-myokine secreted by muscles during exercise, and serum creatine kinase (CK) which is a marker of muscle damage, show changes in their levels with hypo and hyperthyroidism in different species. Objective: To evaluate the levels of both serum irisin and serum creatine kinase in hypo- and hyperthyroid rats, and to illustrate the relationship between their levels and thyroid function tests. Methods: This study was performed on 30 adult healthy male local strain albino rats that were divided into three equal groups: Group I (Control Euthyroid group): Fed on commercial rat laboratory chow, Group II (Hypothyroid group): Hypothyroidism was induced by administration of propylthiouracil, and Group III ( Hyperthyroid group): Hyperthyroidism was induced by administration of T4. BMI in each group was calculated at the end of the experiment. Hormonal assay was performed to measure serum levels of TSH, FT3, FT4, insulin, glucose, irisin and CK. Results: Serum irisin was negatively correlated with TSH levels, and positively correlated with FT3 and FT4 levels in both hypo-and hyperthyroid groups. However, serum CK was positively correlated with TSH levels and negatively correlated with FT3 and FT4 levels in both hypo-and hyperthyroid groups. Also, a negative correlation between serum irisin and serum CK was recorded in both cases of thyroid dysfunction. Conclusions: Serum irisin level decreased in hypothyroid and increased in hyperthyroid rats. At the same time, serum CK level increased in hypothyroid and decreased in hyperthyroid rats. Both serum irisin and CK levels may be considered as parameters for diagnosis of both hypo-and hyperthyroidism in rats.

Gene expression of T3-regulated genes in a mouse model of the human thyroid hormone resistance

AimsTo understand how thyroid hormone (TH) regulates tissue-specific gene expression in patients with the syndrome of resistance to TH (RTHβ), we used a mouse model that replicates the human RTHβ, specifically the ∆337T mutation in the thyroid hormone receptor β (THRβ). Main methodsWe investigated the expression of key TH target genes in the pituitary and liver of TRβ∆337T and wild type THRβ mice by qPCR before and after a T3 suppression test consisting of the administration of increasing concentrations of T3 to hypothyroid mice. Key findingsPituitary Tshb and Cga expression decreased and Gh expression increased in TRβ∆337T mice after T3 suppression. The stimulation of positively regulated TH genes was heterogeneous in the liver. Levels of liver Me1 and Thsrp were elevated in TRβ∆337T mice after T3 administration. Slc16a2 and Gpd2 did not respond to T3 stimulation in the liver of TRβ∆337T mice whereas Dio1 response was lower than that observed in WT mice. Moreover, although Chdh and Upd1 genes were negatively regulated in the liver, the expression of these genes was elevated after T3 suppression. We did not observe significant changes in THRα expression in the liver and pituitary, while THRβ levels were diminished in the pituitary and increased in the liver. SignificanceUsing a model expressing a THRβ unable to bind T3, we showed the expression pattern of liver negative and positive regulated genes by T3.

3,5,3'-Triiodo-L-Thyronine- and 3,5-Diiodo-L-Thyronine- Affected Metabolic Pathways in Liver of LDL Receptor Deficient Mice.

3,5,3′-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2), when administered to a model of familial hypercholesterolemia, i.e., low density lipoprotein receptor (LDLr)-knockout (Ldlr−/−) mice fed with a Western type diet (WTD), dramatically reduce circulating total and very low-density lipoprotein/LDL cholesterol with decreased liver apolipoprotein B (ApoB) production. The aim of the study was to highlight putative molecular mechanisms to manage cholesterol levels in the absence of LDLr. A comprehensive comparative profiling of changes in expression of soluble proteins in livers from Ldlr−/− mice treated with either T3 or T2 was performed. From a total proteome of 450 liver proteins, 25 identified proteins were affected by both T2 and T3, 18 only by T3 and 9 only by T2. Using in silico analyses, an overlap was observed with 11/14 pathways common to both iodothyronines, with T2 and T3 preferentially altering sub-networks centered around hepatocyte nuclear factor 4 α (HNF4α) and peroxisome proliferator-activated receptor α (PPARα), respectively. Both T2 and T3 administration significantly reduced nuclear HNF4α protein content, while T2, but not T3, decreased the expression levels of the HNFα transcriptional coactivator PGC-1α. Lower PPARα levels were found only following T3 treatment while both T3 and T2 lowered liver X receptor α (LXRα) nuclear content. Overall, this study, although it was not meant to investigate the use of T2 and T3 as a therapeutic agent, provides novel insights into the regulation of hepatic metabolic pathways involved in T3- and T2-driven cholesterol reduction in Ldlr−/− mice.

The effects of intra-hippocampal L-thyroxine infusion on long-term potentiation and long-term depression: A possible role for the αvβ3 integrin receptor.

Although the effects of long-term experimental dysthyroidism on long-term potentiation (LTP) and long-term depression (LTD) have been documented, the relationship between LTP/LTD and acute administration of L-thyroxine (T4) has not been described. Here, we investigated the effects of intra-hippocampal administration of T4 on synaptic plasticity in the dentate gyrus of the hippocampal formation. After a 15-minute baseline recording, LTP and LTD were induced by application of high- and low-frequency stimulation protocols, respectively. Infusions of saline or T4 and tetraiodothyroacetic acid (tetrac), a T4 analog that inhibits binding of iodothyronines to the integrin αvβ3 receptor, either alone or together, were made during the stimulation protocols. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes, between 55 to 60 minutes, were used as a measure of the LTP/LTD magnitude and were analyzed by two-way univariate ANOVA with T4 and tetrac as between-subjects factors. The input-output curves of the infusion groups were comparable to each other, as shown by the non significant interaction observed between stimulus intensity and infused drug. The magnitude of the LTP in T4-infused rats was significantly lower as compared to saline-infused rats. Both the PS amplitude and the EPSP slope were depressed more markedly with T4 infusion than with saline, tetrac, and T4 + tetrac infusion. Data of this study provide in vivo evidence that T4 can promote LTD over LTP via the integrin αvβ3 receptor, and that the effect of endogenous T4 on this receptor can be suppressed by tetrac in the hippocampus. © 2016 Wiley Periodicals, Inc.

Effects of thyroid hormones on aortic tissue after myocardial infarction in rats

Studies have shown a cardioprotective role of thyroid hormones (THs) in cardiac remodeling after acute myocardial infarction (MI). However, there is no data in the literature examining the influence of TH administration on the aortic tissue in an animal model of MI. This study aimed to evaluate the effects of thyroid hormones on the aorta after MI. Male Wistar rats were divided into a sham group (SHAM), infarcted group (AMI), sham+TH (SHAMT) and AMI+TH (AMIT). After MI, the animals received T3 and T4 (2 and 8μg/100g/day, respectively) by oral gavage for 12 days. Later, the animals underwent echocardiography and euthanasia and the aorta was collected for molecular and biochemical analysis. T3 and T4 administration increased the expression of the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1α (HIF-1α) in the aorta of AMIT rats when compared with AMI. With respect to TH receptors, AMI rats presented a decrease in TRβ levels, which was prevented by the hormonal administration. In AMIT rats, both TRα and TRβ levels were increased when compared with the AMI group. Reactive oxygen species levels and NADPH oxidase activity were decreased in both treated groups when compared with the non-treated animals. TH administration after MI may improve angiogenic signaling in the aorta as well as the responsiveness of this vessel to T3 and T4. These positive effects in the aorta may result in additional protection for the cardiovascular system in the context of cardiac ischaemic injury.

Metabolic Effects of Chronic T3 Administration in the Hypothalamic Paraventricular and Ventromedial Nucleus in Male Rats.

Thyroid hormone is a key regulator of energy metabolism. Apart from its direct effects on peripheral metabolism, thyroid hormone exerts acute metabolic effects via distinct nuclei within the hypothalamus. Recently we developed a method for chronic and local intrahypothalamic T3 administration in rats. The present study evaluated the metabolic effects of T3 delivered during either 7 or 28 days to the paraventricular or ventromedial nucleus of the hypothalamus (PVN or VMH). T3 administration for 7 days in the PVN decreased only plasma T3. There were no effects on body weight, food intake, plasma glucose concentrations, energy expenditure, locomotor activity, and respiratory exchange rate. In the liver and brown adipose tissue (BAT), there were no changes in mRNA expression of genes involved in glucose metabolism and thermogenesis. T3 administration for 7 days in the VMH did not change any of these parameters. T3 administration for 28 days in the PVN decreased food intake without affecting body weight, glucose concentrations, and body temperature. Liver and BAT gene expression was unaltered, except for decreased liver Dio1 mRNA. T3 administration for 28 days in the VMH did not affect liver and BAT mRNA expression, body weight, food intake, and body temperature, whereas blood glucose concentrations were slightly lower. In conclusion, we showed that chronic T3 administration to the PVN or VMH does not affect energy metabolism in a major way. Our results imply that the effects of intrahypothalamic T3 administration on metabolism largely depend on the duration of treatment.

T3 enhances Ang2 in rat aorta in myocardial I/R: comparison with left ventricle.

Angiogenesis is important for recovery after tissue damage in myocardial ischemia/reperfusion, and tri-iodothyronine (T3) has documented effects on angiogenesis. The angiopoietins 1/2 and tyrosine kinase receptor represent an essential system in angiogenesis controlling endothelial cell survival and vascular maturation. Recently, in a 3-day ischemia/reperfusion rat model, the infusion of a low dose of T3 improved the post-ischemic recovery of cardiac function.Adopting this model, our study aimed to investigate the effects of T3 on the capillary index and the expression of angiogenic genes as the angiopoietins 1/2 and tyrosine kinase receptor system, in the thoracic aorta and in the left ventricle. In the thoracic aorta, T3 infusion significantly improved the angiogenic sprouting and angiopoietin 2 expression. Instead, Sham-T3 group did not show any significant increment of capillary density and angiopoietin 2 expression. In the area at risk (AAR) of the left ventricle, T3 infusion did not increase capillary density but restored levels of angiopoietin 1, which were reduced in I/R group. Angiopoietin 2 levels were similar to Sham group and unchanged by T3 administration. In the remote zone, T3 induced a significant increment of both angiopoietin 1/2. In conclusion, T3 infusion induced a different response of angiopoietin 1/2 between the ventricle (the AAR and the remote zone) and the thoracic aorta, probably reflecting the different action of angiopoietin 1/2 in cardiomyocytes and endothelial cells. Overall, these data suggest a new aspect of T3-mediated cardioprotection through angiogenesis.