Pituitary Thyrotropin Research Articles

The pituitary–thyroid axis during the parr–smolt transformation of Coho salmon, Oncorhynchus kisutch: Quantification of TSH β mRNA, TSH, and thyroid hormones

The objective of this investigation was to quantify pituitary thyroid stimulating hormone (TSH) β mRNA, pituitary and plasma TSH and plasma thyroid hormone levels during the parr–smolt transformation of Coho salmon that occurs in spring from February to May. The status of the pituitary–thyroid axis was assessed using an RNase protection assay for pituitary TSH β mRNA and radioimmunoassays for salmon pituitary and plasma TSH and thyroid hormones. TSH β mRNA was highest during late winter (February) (4.9 pg/μg DNA) and gradually declined during spring (2.3 pg/μg DNA). In contrast, pituitary and plasma TSH levels showed a small, but statistically non-significant change during smoltification. Despite minimal change in plasma TSH levels, characteristically large increases in plasma T4 (January-3.3 ng/ml to April-10.2 ng/ml) and significant, but modest increases in plasma T3 (February-2.4 ng/ml to April-5.8 ng/ml) were observed. Regression analysis showed a significant positive relationship between plasma T4 and T3 and negative relationship between plasma T3 and pituitary TSH β mRNA. However, all other relations were not significant. These data suggest a significant role for peripheral regulation (i.e. T4–T3 conversion, change in tissue sensitivity, hormone degradation rate) as well as evidence of central regulation via negative feedback at the level of the pituitary gland in regulation of thyroid activity in salmon. Furthermore, the increased thyroid sensitivity to TSH (shown previously), in the face of relatively constant plasma TSH levels, may be the major factor responsible for the increased thyroid activity observed during smoltification.

Thyroid-stimulating hormone (TSH): Measurement of intracellular, secreted, and circulating hormone in Xenopus laevis and Xenopus tropicalis

Thyroid-stimulating hormone (TSH) is an important regulator of the hypothalamic–pituitary–thyroid (HPT) axis in Xenopus laevis. To evaluate the role of this hormone on developing tadpoles, immunologically-based Western blots and sandwich ELISAs were developed for measuring intracellular (within pituitaries), secreted ( ex vivo pituitary culture), and circulating (serum) amounts. Despite the small size of the tadpoles, these methods were able to easily measure intracellular and secreted TSH, and circulating TSH was measurable in situations where high levels were induced. The method was validated after obtaining a highly purified and enriched TSH sample using anti-TSH-β antibodies conjugated to magnetic beads. Subsequent mass-spectrometric analysis of the bands from SDS–PAGE and Western procedures identified the presence of amino acid sequences corresponding to TSH subunits. The purified sample was also used to prepare standard curves for quantitative analysis. The Western and ELISA methods had limits of detection in the low nanogram range. While the majority of the developmental work for these methods was done with X. laevis, the methods also detected TSH in Xenopus tropicalis. To our knowledge this is the first report of a specific detection method for TSH in these species, and the first to measure circulating TSH in amphibians. Examples of the utility of the methods include measuring a gradual increase in pituitary TSH at key stages of development, peaking at stages 58–62; the suppression of TSH secretion from cultured pituitaries in the presence of thyroid hormone (T4); and increases in serum TSH following thyroidectomy.

L-thyroxine treatment in primary hypothyroidism does not increase the content of free triiodothyronine in cerebrospinal fluid: A pilot study

The association between cerebrospinal fluid (CSF) and serum concentration of thyroid hormones and pituitary thyrotropin stimulating hormone (TSH) was studied in nine hypothyroid patients (HT) before and in seven after L-thyroxine treatment. With L-thyroxine, median free T4 increased 4-fold in serum (3.5 pmol/L vs 17.5 pmol/L) and 3-fold in CSF, (3.9pmol/L vs 11.5 pmol/L). Correspondingly, total T3 in serum increased two-fold (0.9 nmol/L vs 2.2 nmol/L). Unexpectedly, free T3 concentration in CSF was similar (1.5 pmol/L vs.1.5 pmol/L) before and during treatment. In HT, TSH in serum correlated with TSH in CSF as did free T4 in serum and in CSF. During L-thyroxine, the correlation with TSH in serum and CSF remained. Likewise, the free T4 concentration in serum correlated with that in CSF. However, no correlation was found between T3 in serum and free T3 in CSF. It seems evident that free T4 in serum equilibrates with that in the CSF both in the HT and during L-thyroxine. Despite a two-fold increase in total serum T3, free T3 in CSF remained unchanged, which agrees with previous results in rats showing that T3 is less exchangeable between serum and CSF. Alternatively, an accelerated conversion of T4 to T3 might have maintained the concentration of T3, due to strongly increased levels of TSH found in the hypothyroid state. The notion that free T4 in serum reflects the CSF concentration of free T4 is consistent with previous reports from studies in animals.

Neuroendocrine control of thyroid‐stimulating hormone and adrenocorticotropic hormone in amphibians

Event Abstract Back to Event Neuroendocrine control of thyroid‐stimulating hormone and adrenocorticotropic hormone in amphibians Reiko Okada1*, Kazutoshi Yamamoto2, Itaru Hasunuma3, Shigeyasu Tanaka1 and Sakae Kikuyama2 1 Shizuoka University, Integrated Bioscience Section, Graduate School of Science and Technology, Japan 2 Waseda University, Department of Biology, Faculty of Education and Integrated Arts and Science, Japan 3 Toho University, Department of Biology, Faculty of Science, Japan In non-mammalian vertebrates, pituitary thyrotropin (TSH) secretion is considered to be regulated by multiple hypothalamic neuropeptides such as TSH-releasing hormone (TRH), corticotropin-releasing factor (CRF), gonadotropin-releasing hormone, pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and somatostatin. The main TSH-releasing factor varies according to the animal classes and the developmental stages. By performing in vitro experiments combined with specific radioimmunoassay for bullfrog TSH, we demonstrated that the frog CRF potently stimulates the release of TSH from both adult and larval bullfrog pituitary cells, whereas TRH moderately stimulates the TSH release from adult pituitary cells but not from larval ones and that the action of CRF is mediated by the CRF receptor 2. It was also shown that TSH-releasing activity in the bullfrog hypothalamic extract is profoundly diminished by a CRF receptor antagonist, suggesting that endogenous CRF contributes as a main TSH-releasing factor. On the other hand, both CRF and arginine-vasotocin (AVT)/arginine-vasopressin (AVP) have been reported to stimulate the release of adrenocorticotropic hormone (ACTH) from the pituitary of various vertebrates. In order to compare the potency of both peptides in terms of stimulating the ACTH release, experiments were conducted using dispersed bullfrog pituitary cells. The amount of ACTH released into the culture medium, as measured by a newly developed time-resolved fluoroimmunoassay for frog ACTH, was much higher when the pituitary cells were incubated in the presence of AVT than when they were incubated with CRF. This raised possibility that in amphibians, AVT rather than CRF is the main ACTH-releasing factor. Keywords: ACTH, amphibian, AVT, CRF, TSH Conference: ISAREN 2011: 7th International Symposium on Amphibian and Reptilian Endocrinology and Neurobiology, Ann Arbor, United States, 11 Jul - 13 Jul, 2011. Presentation Type: Invited Symposium Topic: Abstracts Citation: Okada R, Yamamoto K, Hasunuma I, Tanaka S and Kikuyama S (2011). Neuroendocrine control of thyroid‐stimulating hormone and adrenocorticotropic hormone in amphibians. Front. Endocrinol. Conference Abstract: ISAREN 2011: 7th International Symposium on Amphibian and Reptilian Endocrinology and Neurobiology. doi: 10.3389/conf.fendo.2011.03.00036 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jul 2011; Published Online: 09 Aug 2011. * Correspondence: Dr. Reiko Okada, Shizuoka University, Integrated Bioscience Section, Graduate School of Science and Technology, Shizuoka, 422-8529, Japan, drokada@ipc.shizuoka.ac.jp Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Reiko Okada Kazutoshi Yamamoto Itaru Hasunuma Shigeyasu Tanaka Sakae Kikuyama Google Reiko Okada Kazutoshi Yamamoto Itaru Hasunuma Shigeyasu Tanaka Sakae Kikuyama Google Scholar Reiko Okada Kazutoshi Yamamoto Itaru Hasunuma Shigeyasu Tanaka Sakae Kikuyama PubMed Reiko Okada Kazutoshi Yamamoto Itaru Hasunuma Shigeyasu Tanaka Sakae Kikuyama Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Ontogenic characterization of gene expression in the developing neuroendocrine system of the chick

The neuroendocrine system consists of five major hypothalamic-pituitary hormone axes that regulate several important metabolic processes, and it develops in all vertebrates during embryogenesis. In order to define initiation and establishment of these five axes, mRNA expression profiles of hypothalamic releasing and release-inhibiting factors, their pituitary receptors, and pituitary hormones were characterized during the second half of embryogenesis and first week post-hatch in the chick. Axis initiation was defined as the age when pituitary hormone mRNA levels began to increase substantially, and establishment was defined as the age when mRNA for all components had reached maximum expression levels. The adrenocorticotropic axis appears established by e12, as there were no major increases in gene expression after that age. Hypothalamic thyrotropin-releasing hormone and pituitary thyroid-stimulating hormone β-subunit increased between e10 and e18, indicating establishment of the thyrotropic axis during this period. Pituitary growth hormone substantially increased on e16, and hypothalamic growth hormone-releasing hormone did not increase until e20, indicating that somatotropic axis activity is established late in embryonic development. Lactotropic axis initiation is evident just prior to hatch, as pituitary prolactin and vasoactive intestinal peptide receptor 1 did not increase until e18 and e20, respectively. Hypothalamic gonadotropin-releasing hormone 1 increased after hatch, and pituitary luteinizing hormone β-subunit expression remained low until d3, indicating the gonadotropic axis is not fully functional until after hatching. This study is the first to characterize major hypothalamic and pituitary components of all five neuroendocrine axes simultaneously and considerably increases our understanding of neuroendocrine system establishment during development.

A Review on Hyperthyroidism: Thyrotoxicosis under Surveillance

Thyrotoxicosis exhibit collective clinical manifestation, caused by excessive serum thyroid hormones particularity thyroxin. The clinical signs and symptoms included general alteration of metabolic process leading to weight loss fatigue and weakness and some specific disorders such as cardiovascular, neuromuscular reproductive gastrointestinal dermatological and bone disorders. The diagnosis of thyrotoxicosis relay on the thyroid function test carried out by the laboratory serum measurement of thyroxin, triiodothyronine and thyroid stimulating hormones accompanied by other para-medical examinations suggested by clinicians and endociologicst. In thyrotoxicosis serum level of thyroid hormones and thyroxin in particular elevated accompanied by pituitary thyroid stimulating hormone suppression reaching to undetectable level in sever thyrotoxicosis. Among the most common cause of thyrotoxicosis are, thyroid autoimmunity diseases thyroid toxic, adenoma toxic nodular and multinodular hyperthyroidism. The main aim behind this review is to explore the clinical manifestation, the causative factors, diagnosis, metabolic disorder occur due to thyrotoxicosis.

Suppressive effects of genistein and daidzein on pituitary–thyroid axis in orchidectomized middle-aged rats

High intake of soybean phytoestrogens, isoflavones genistein (G) and daidzein (D), has been associated with health benefits. However, isoflavones were reported to affect adversely thyroid function in the presence of other goitrogenic factors. As the thyroid gland becomes functionally impaired with age, we examined whether supplementary doses of G or D would affect morphology and function of pituitary-thyroid axis in middle-aged male rats. Sixteen-month-old orchidectomized Wistar rats were treated with 10 mg/kg of either G or D, while the control sham-operated and orchidectomized group received just the vehicle for three weeks. The animals were fed soy-free diet with increased iodine content, and killed 24 h after the last treatment. Their pituitaries and thyroids were excised and prepared for further immunohistochemical and morphometric investigation. The concentrations of thyroid-stimulating hormone (TSH), total T(4) and T(3), in the serum were determined. In both isoflavone-treated groups, pituitary TSH-immunopositive cells had increased cellular volume and relative volume density (P < 0.05), as well as increased serum TSH levels (P < 0.05) in comparison to the controls; their thyroid tissue was characterized by increased volume of thyroglobulin-immunopositive epithelium (P < 0.05), epithelial height and index of activation rate (P < 0.05), while the volume of luminal colloid, and total serum T(4) and T(3) levels decreased (P < 0.05) in comparison to the controls. In conclusion, this study provides the first direct evidence that both G and D can induce microfollicular changes in the thyroid tissue and reduce the level of thyroid hormones in Orx middle-aged male rats, a model of andropause. This reduction consequently led to a feedback stimulation of pituitary TSH cells. The detected stimulatory effect was higher in the daidzein-treated rats.

Unbiased stereological estimation of the rat fetal pituitary volume and of the total number and volume of TSH cells after maternal dexamethasone application

Glucocorticoids have an inhibitory influence on proliferation activity of the pituitary cells while stimulating apoptosis. Therefore, it was hypothesized that the synthetic glucocorticoid, dexamethasone (DX), has an inhibitory influence on the number of thyroid-stimulating hormone (TSH) cells during fetal development. The effects of maternal administration of DX on stereological parameters of TSH cells, and TSH serum concentration were investigated in 21-day-old rat fetuses. On day 16 of pregnancy, the experimental dams received 1.0 mg DX/kg b.w. subcutaneously, followed by 0.5 mg DX/kg b.w./day on days 17 and 18 of gestation. The control gravid females received the same volume of saline vehicle. TSH cells were stained immunocytochemically by the peroxidase-antiperoxidase (PAP) method. The fetal pituitary volumes were estimated using Cavalieri's principle. A physical disector counting technique in combination with the fractionator sampling method was used for estimation of pituitary TSH cell number. Cell and nuclear volumes were measured with a planar rotator. Maternal DX application was found to cause a significant decrease of pituitary volume and number of TSH cells per pituitary in 21-day-old fetuses in comparison with the control fetuses. TSH cell number expressed per body weight unit declined significantly after maternal DX administration. These results indicate an inhibitory DX influence on proliferative activity of precursors and likely differentiated TSH cells and increased apoptotic prevalence. The histological appearance, volume of TSH cells and TSH serum concentration suggest intensive synthetic activity in TSH cells of DX exposed fetuses.

TSH Isoforms: About a Case of Hypothyroidism in a Down's Syndrome Young Adult

Background. For unknown reasons, the prevalence of thyroid autoimmune disorders is higher in patients with Down's syndrome than in the general population. The present case strongly supports a recent evaluation of propagating screening for thyroid disease in this group of patients to assure early diagnosis of hypothyroidism. Methods. In a 25-year-old man diagnosed with Down's syndrome, clinical manifestations of hypothyroidism were lacking, but profound biochemical abnormalities were found with particularly high levels of thyroid stimulating hormone (TSH). Antigenic properties of TSH were characterized using a panel of anti-TSH antibodies. Results. Technical problems not infrequently associated with TSH measurements are convincingly ruled out. Antigenic characterization of the patient's circulating TSH revealed circulating forms of TSH different from pituitary TSH which closely resembled TSH recombinant human hormone. Conclusions. It appears counterintuitive that the bioactivity of TSH decreases in the hypothyroid state as higher bioactivity of TSH is anticipated in hypothyroidism promoted by an increased hypothalamic TRH drive. In contrast, diminished negative thyroid hormone feedback will enhance posttranslational glycosylation of TSH subunits and increase sialylation of the carbohydrate side chains. Both exert a negative effect on TSH bioactivity, only compensated by the very high levels of the hormone as in the present case.

Effect of thymus on the thyroid and pituitary thyrotropic function.

Thymus inflammation induced in infantile guinea pigs and rabbits by administration of melted paraffin drops into the thymic parenchyma resulted in enhancement of the thyroid functional activity. Thymosin injections provoked an identical effect. In both variants of these experiments the pituitary thyrotropin level remained within the norm. Hence, the pituitary thyrotropic function as in thyrotoxicosis lost the ability of response to enhancement of the thyroid hormone production. This result suggests that the cause of disorganization of the negative feedback between the thyroid and the pituitary thyrotropic function might be attributed to enforcement of the stimulated thymus secretory activity.

Human Female Hair Follicles Are a Direct, Nonclassical Target for Thyroid-Stimulating Hormone

Pituitary thyroid-stimulating hormone (TSH) regulates thyroid hormone synthesis via receptors (TSH-R) expressed on thyroid epithelial cells. As the hair follicle (HF) is uniquely hormone-sensitive and, hypothyroidism with its associated, increased TSH serum levels clinically can lead to hair loss, we asked whether human HFs are a direct target for TSH. Here, we report that normal human scalp skin and microdissected human HFs express TSH-R mRNA. TSH-R-like immunoreactivity is limited to the mesenchymal skin compartments in situ. TSH may alter HF mesenchymal functions, as it upregulates alpha-smooth muscle actin expression in HF fibroblasts. TSH-R stimulation by its natural ligand in organ culture changes the expression of several genes of human scalp HFs (for example keratin K5), upregulates the transcription of classical TSH target genes and enhances cAMP production. Although the functional role of TSH in human HF biology awaits further dissection, these findings document that intracutaneous TSH-Rs are fully functional in situ and that HFs of female individuals are direct targets for nonclassical, extrathyroidal TSH bioregulation. This suggests that organ-cultured scalp HFs provide an instructive and physiologically relevant human model for exploring nonclassical functions of TSH, in and beyond the skin.

Thyroid Hormone Receptor β Mediates Acute Illness‐Induced Alterations in Central Thyroid Hormone Metabolism

Acute illness in mice profoundly affects thyroid hormone metabolism in the hypothalamus and pituitary gland. It remains unknown whether the thyroid hormone receptor (TR)-β is involved in these changes. In the present study, we investigated central thyroid hormone metabolism during lipopolysaccharide (LPS)-induced illness in TRβ(-/-) mice compared to wild-type (WT) mice. We administered a sublethal dose of LPS or saline to TRβ(-/-) and WT mice. TRβ(-/-) mice displayed higher basal levels of serum triiodothyronine (T(3)) and thyroxine (T(4)) compared to WT, reflecting thyroid hormone resistance. In the periventricular area of the hypothalamus, we observed a marked decrease in thyrotrophin-releasing hormone (TRH) mRNA expression in TRβ(-/-) and WT mice at t = 4 h, coinciding with the peak in plasma corticosterone. The decrease in TRH mRNA persisted in WT, but not in TRβ(-/-) mice at t = 24 h. By contrast, the increase of type 2 deiodinase (D2) mRNA already present at 4 h after LPS remained significant at 24 h in TRβ(-/-), but not in WT mice. LPS decreased pituitary thyroid-stimulating hormone β mRNA expression in WT at 24 h but not in TRβ(-/-) mice. The peak in pituitary D2 expression at t = 4 h in WT was absent in TRβ(-/-) mice. The relative decrease in plasma T(3) and T(4) upon LPS treatment was similar in both strains, although, at t = 24 h, plasma T(3) tended to be restored in TRβ(-/-) mice. Our results suggest that TRβ is involved in suppression of the central component of the hypothalamic-pituitary-thyroid axis in acute illness.

Influence of genetic factors on the result of therapy for diffuse euthyroid goiter

The purpose of the present study was to investigate a relationship between the distribution of genotypes of the polymorphic markers TSHR (rs3783949, A/C substitution), NIS (rs7250346, C/G substitution), DUOXI (rs2467825, A/G substitution), DUOX2 (rs71713669, G/T substitution), and TRO (rs!7091737, G/T substitution) genes and the result of treatment for diffuse euthyroid goiter (DEG) using two regimens: monotherapy with iodine preparations and combined therapy with iodine and levothyroxine. To identify a more effective and safe treatment for DEG, the authors compared thyroid volume, the levels of pituitary thyroid-stimulating hormone and thyroid peroxidase antibodies in two groups: 1) monotherapy with KI (200 pg/day) (n = 40) and 1) combined therapy with KI (100 pg) + L-T4(lpg/kg/day) (n = 41). According to the result of treatment, each group was divided into 2 subgroups: "fair result" and "poor result" (the thyroid volume failed to achieve the normal range or continued to increase). Correlation analysis was made to assess a relationship between the polymorphism of the genes and the result of therapy for DEG. There was a significant correlation between the distribution of genotypes of the polymorphic marker the TSHR gene and the result of treatment for DES in the monotherapy group: there were prevalent AA + AC and CC genotypes with fair and poor results, respectively. There was no significant correlation between the distribution of the genotypes of the study polymorphic markers and the result of treatment using the combined therapy. Thus, the result of treatment for DES via monotherapy with iodine preparations may depend on genetic factors.

Skeletal morphofunctional considerations and the pituitary-thyroid axis

The past decade has unraveled novel molecular mechanisms not only of skeletal remodeling, which is the process by which the skeleton is restructured throughout adult life, but also the precision by which the skeleton is put together during embryogenesis and later modeled during growth. It is now possible to delete single genes in individual cells and during specified periods of life. This has allowed us to pin down specific molecular events that underlie individual cellular processes, and also importantly, to identify molecular defects underlying disorders of skeletal morphogenesis and remodeling. Particularly novel has been the demonstration of cross-talk, some of which is humoral, between the skeleton and organs as diverse as the brain, pituitary, and even adipose tissue and pancreas. The current review describes these molecular mechanisms in relation to the way thyroid hormones, and the pituitary hormone thyrotropin (TSH), regulate skeletal morphogenesis and remodeling.

Thyroid dysfunction and kidney disease

Thyroid hormones (TH) are essential for an adequate growth and development of the kidney. Conversely, the kidney is not only an organ for metabolism and elimination of TH, but also a target organ of some of the iodothyronines' actions. Thyroid dysfunction causes remarkable changes in glomerular and tubular functions and electrolyte and water homeostasis. Hypothyroidism is accompanied by a decrease in glomerular filtration, hyponatremia, and an alteration of the ability for water excretion. Excessive levels of TH generate an increase in glomerular filtration rate and renal plasma flow. Renal disease, in turn, leads to significant changes in thyroid function. The association of different types of glomerulopathies with both hyper- and hypofunction of the thyroid has been reported. Less frequently, tubulointerstitial disease has been associated with functional thyroid disorders. Nephrotic syndrome is accompanied by changes in the concentrations of TH due primarily to loss of protein in the urine. Acute kidney injury and chronic kidney disease are accompanied by notable effects on the hypothalamus-pituitary-thyroid axis. The secretion of pituitary thyrotropin (TSH) is impaired in uremia. Contrary to other non-thyroidal chronic disease, in uraemic patients it is not unusual to observe the sick euthyroid syndrome with low serum triodothyronine (T(3)) without elevation of reverse T(3) (rT(3)). Some authors have reported associations between thyroid cancer and kidney tumors and each of these organs can develop metastases into the other. Finally, data from recent research suggest that TH, especially T(3), can be considered as a marker for survival in patients with kidney disease.

Multiple endocrine neoplasia type 1–associated thyrotropin-producing pituitary carcinoma: report of a probable de novo example

Pituitary carcinomas are exceedingly rare. At present, the sole diagnostic criterion is metastatic spread, either craniospinal or systemic. There is no agreement on a histologic, immunohistochemical, and/or ultrastructural definition. We report a clinically and morphologically well-documented example of pituitary thyrotropin cell carcinoma in a man with multiple endocrine neoplasia type 1 syndrome. The tumor produced thyrotropin, alpha-subunit, and prolactin and, through electron microscopy, was found to consist solely of Thyrotroph cells. Over a protracted course, craniospinal and systemic metastases were noted. The primary and metastatic deposits of this aggressive tumor were studied. To our knowledge, this tumor is the first reported case of thyrotropin cell carcinoma occurring in association with the multiple endocrine neoplasia type 1 syndrome. The literature regarding thyrotropin carcinomas is reviewed. Based on the study of several biopsies during disease progression, we believe that the carcinoma originated de novo without an intermediary adenoma phase.

Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist #

Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, with a prevalence ranging from 10% to 30%. The use of thyroid hormone receptor (TR) agonists for the treatment of NAFLD has not been considered viable because thyroid hormones increase free fatty acid (FFA) flux from the periphery to the liver, induce hepatic lipogenesis, and therefore could potentially cause steatosis. MB07811 is an orally active HepDirect prodrug of MB07344, a liver-targeted TR-beta agonist. The purpose of these studies was to assess the effects of MB07811 on whole body and liver lipid metabolism of normal rodents and rodent models of hepatic steatosis. In the current studies, MB07811 markedly reduced hepatic steatosis as well as reduced plasma FFA and triglycerides. In contrast to MB07811, T(3) induced adipocyte lipolysis in vitro and in vivo and had a diminished ability to decrease hepatic steatosis. This suggests the influx of FFA from the periphery to the liver may partially counteract the antisteatotic activity of T(3). Clearance of liver lipids by MB07811 results from accelerated hepatic fatty acid oxidation, a known consequence of hepatic TR activation, as reflected by increased hepatic mitochondrial respiration rates, changes in hepatic gene expression, and increased plasma acyl-carnitine levels. Transaminase levels remained unchanged, or were reduced, and no evidence for liver fibrosis or other histological liver damage was observed after treatment with MB07811 for up to 10 weeks. Additionally, MB07811, unlike T(3), did not increase heart weight or decrease pituitary thyroid-stimulating hormone beta (TSHbeta) expression. MB07811 represents a novel class of liver-targeted TR agonists with beneficial low-density lipoprotein cholesterol-lowering properties that may provide additional therapeutic benefit to hyperlipidemic patients with concomitant NAFLD.

Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis

Triiodothyroacetic acid (TRIAC) is a physiological product of triiodothyronine (T(3)) metabolism, with high affinity for T(3) nuclear receptors. Its interest stems from its potential thermogenic effects. Thus this work aimed 1) to clarify these thermogenic effects mediated by TRIAC vs. T(3) in vivo and 2) to determine whether they occurred predominantly in adipose tissues. To examine this, control rats were infused with equimolar T(3) or TRIAC doses (0.8 or 4 nmolx100 g body wt(-1) x day(-1)) or exposed for 48 h to cold. Both T(3) doses and only the highest TRIAC dose inhibited plasma and pituitary thyroid-stimulating hormone (TSH) and thyroxine (T(4)) in plasma and tissues. Interestingly, the lower TRIAC dose marginally inhibited plasma T(4). T(3) infusion increased plasma and tissue T(3) in a tissue-specific manner. The highest TRIAC dose increased TRIAC concentrations in plasma and tissues, decreasing plasma T(3). TRIAC concentrations in tissues were <10% those of T(3). Under cold exposure or high T(3) doses, TRIAC increased only in white adipose tissue (WAT). Remarkably, only the lower TRIAC dose activated thermogenesis, inducing ectopic uncoupling protein (UCP)-1 expression in WAT and maximal increases in UCP-1, UCP-2, and lipoprotein lipase (LPL) expression in brown adipose tissue (BAT), inhibiting UCP-2 in muscle and LPL in WAT. TRIAC, T(3), and cold exposure inhibited leptin secretion and mRNA in WAT. In summary, TRIAC, at low doses, induces thermogenic effects in adipose tissues without concomitant inhibition of TSH or hypothyroxinemia, suggesting a specific role regulating energy balance. This selective effect of TRIAC in adipose tissues might be considered a potential tool to increase energy metabolism.

Fasting-Induced Changes in the Hypothalamus–Pituitary–Thyroid Axis

Fasting induces profound changes in the hypothalamus-pituitary-thyroid (HPT) axis. The alterations observed in humans and rodents are similar in many ways, although they may be more pronounced and more acute in rodents. The molecular mechanisms underlying the resetting of HPT axis regulation in the framework of caloric deprivation are still incompletely understood. Fascinating studies in rats and mice have shown a dramatic downregulation of thyrotropin-releasing hormone (TRH) gene expression in hypophysiotropic paraventricular nucleus (PVN) neurons during fasting. Direct and indirect effects of decreased serum leptin, as well as effects of increased local triiodothyronine (T3) concentrations, in the hypothalamus during food deprivation contribute to the decreased activity of TRH neurons in the PVN. However, the relative contributions of these complex determinants remain to be defined in more detail. Pituitary thyroid-stimulating hormone (TSH) beta mRNA expression decreases during fasting, and this may be relatively independent of leptin and/or TRH, since leptin administration in this setting does not fully restore pituitary TSH expression, while it does restore TRH expression in the PVN. There may be a role for pituitary peptides, such as neuromedin B, in altered TSH gene expression during fasting. The observed decrease in serum thyroid hormone concentrations results to some extent from diminished thyroidal secretion of thyroid hormones, especially in rodents. Decreased thyroxine (T4) and T3 contribute to the downregulation of T3-responsive genes such as liver D1. The overall result of these complex HPT axis changes in various tissues during fasting is downregulation of the HPT axis, which is assumed to represent an energy-saving mechanism, instrumental in times of food shortage.

Neonatal Low-Protein Diet Changes Deiodinase Activities and Pituitary TSH Response to TRH in Adult Rats

Protein malnutrition during neonatal programs for a lower body weight and hyperthyroidism in the adult offspring were analyzed. Liver deiodinase is increased in such animals, contributing to the high serum triiodothyronine (T3) levels. The level of deiodinase activities in other tissues is unknown. We analyzed the effect of maternal protein restriction during lactation on thyroid, skeletal muscle, and pituitary deiodinase activities in the adult offspring. For pituitary evaluation, we studied the in vitro, thyrotropin-releasing hormone (TRH)-stimulated thyroid-stimulating hormone (TSH) secretion. Lactating Wistar rats and their pups were divided into a control (C) group, fed a normal diet (23% protein), and a protein-restricted (PR) group, fed a diet containing 8% protein. At weaning, pups in both groups were fed a normal diet until 180 days old. The pituitary gland was incubated before and after TRH stimulation, and released TSH was measured by radioimmunoassay. Deiodinase activities (D1 and D2) were determined by release of (125)I from [(125)I]reverse triiodothyronine (rT3). Maternal protein malnutrition during lactation programs the adult offspring for lower muscle D2 (-43%, P<0.05) and higher muscle D1 (+83%, P<0.05) activities without changes in thyroidal deiodinase activities, higher pituitary D2 activity (1.5 times, P<0.05), and lower TSH response to in vitro TRH (-56%, P<0.05). The evaluations showed that the lower in vivo TSH detected in adult PR hyperthyroid offspring, programmed by neonatal undernutrition, may be caused by an increment of pituitary deiodination. As described for liver, higher skeletal muscle D1 activity suggests a hyperthyroid status. Our data broaden the knowledge about the adaptive changes to malnutrition during lactation and reinforce the concept of neonatal programming of the thyroid function.