Welcome to Thyroid Research

Welcome to the first issue of Thyroid Research, a new journal published by BioMed Central, which aims at providing a platform for both researchers and clinicians to discuss a broad spectrum of thyroidology and related issues. These include physiological mechanisms of thyroid hormone action, secretory regulations, immunological and genetic aspects and, finally, news and information on state-of-the-art diagnostic equipment and treatment protocols for more effective management of thyroid disorders

Selenium in biology: Facts and medical perspectives

Several decades after the discovery of setenium as an essential trace element in vertebrates approximately 20 eukaryotic and more than 15 prokaryotic selenoproteins containing the 21(st) proteinogenic amino acid, selenocysteine, have been identified, partially characterized or cloned from several species. Many of these proteins are involved in redox reactions with selenocysteine acting as an essential component of the catalytic cycle. Enzyme activities have been assigned to the glutathione peroxidase family, to the thioredoxin reductases, which were recently identified as selenoproteins, to the iodothyronine deiodinases, which metabolize thyroid hormones, and to the selenophosphate synthetase 2, which is involved in selenoprotein biosynthesis. Prokaryotic selenoproteins catalyze redox reactions and formation of selenoethers in (stress-induced) metabolism and energy production of E. coli, of the clostridial cluster XI and of other prokaryotes. Apart from the specific and complex biosynthesis of selenocysteine, selenium also reversibly binds to proteins, is incorporated into selenomethionine in bacteria, yeast and higher plants, or posttranslationally modifies a catalytically essential cysteine residue of CO dehydrogenase. Expression of individual eukaryotic selenoproteins exhibits high tissue specificity, depends on selenium availability, in some cases is regulated by hormones, and if impaired contributes to several pathological conditions. Disturbance of selenoprotein expression or function is associated with deficiency syndromes (Keshan and Kashin-Beck disease), might contribute to tumorigenesis and atherosclerosis, is altered in several bacterial and viral infections, and leads to infertility in male rodents

Uptake and turnover of mono-iodinated thyroid hormone metabolites by PCCL3 thyrocytes

Tyrosine and phenolic ring de-iodination of thyroid hormones (TH) is crucial for regulating their physiological activity. Furthermore, reactions such as de-carboxylation to thyronamines (TAM) and de-amination to thyroacetic acids (TAc) produce TH metabolites (THM) with distinct biological properties. This needs to be considered when studying effects of TH and THM. The accurate and precise quantitative analysis of TH and THM in cell culture supernatants and cell lysates are key procedures required for studying the in vitro metabolism of TH. We report here the development of a liquid-liquid extraction/isotope dilution-liquid chromatography-electrospray tandem mass spectrometry (LC- MS/MS) method for the quantification of 9 thyronines (TN) and 6 TAM in human hepatocellular carcinoma Hep G2 cell lysate extracts. In addition, we adapted the method to quantify TH, TAM and TAc, in cell lysates of FBS-depleted rat thyroid epithelium PCCL3 cells. The methods for both cell lines were validated by rigorous assessment of linearity, limits of quantification and detection (LLOQ and LLOD respectively), intra- and inter-day accuracy, precision, process efficiency (PE), matrix effect (ME) and relative recovery (RE). Calibration curves covering 11 concentrations (based on 400 μl of lysate) were linear in the range 0.016–50 nM and 0.010–50 nM for Hep G2 and PCCL3 cells respectively. The lower limits of quantification were in the range 0.031 to 1 nM. We applied the PCCL3 version of the LC-MS/MS method to the analysis of lysed cell extracts from PCCL3 cells that had been incubated with 3-iodo-L-thyronine (T1), 3-iodothyronamine (3-T1AM) and 3-iodothyroacetic acid (3-T1Ac). Over the course of 30 minutes incubation 3-T1AM was de-iodinated to 4-[4-(2-aminoethylphenoxy)]phenol (thyronamine, T0AM) and de-aminated to 3-T1Ac respectively, whilst T1 underwent de-iodination to T0. This data indicates avid metabolism of these mono-iodinated compounds and the utility of LC-MS/MS to quantify such cellular metabolism

Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System

The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics

Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice

The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal 18F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo14C-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. 18F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced 18F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively

Differences in Mouse Hepatic Thyroid Hormone Transporter Expression with Age and Hyperthyroidism

Background: Clinical features of thyroid dysfunction vary with age, and an oligosymptomatic presentation of hyperthyroidism is frequently observed in the elderly. This suggests age modulation of thyroid hormone (TH) action, which may occur, for example, by alterations in TH production, metabolism and/or TH action in target organs. Objectives: In this paper, we address possible changes in TH transporter expression in liver tissues as a mechanism of age-dependent variation in TH action. Methods: Chronic hyperthyroidism was induced in 4- and 20-month-old C57BL6/NTac male mice (n = 8-10) by intraperitoneal injections of 1 µg/g body weight L-thyroxine (T4) every 48 h over 7 weeks. Control animals were injected with PBS. Total RNA was isolated from liver samples for analysis of the TH transporter and TH-responsive gene expression. TH concentrations were determined in mice sera. Results: Baseline serum free T4 (fT4) concentrations were significantly higher in euthyroid young compared to old mice. T4 treatment increased total T4, fT4 and free triiodothyronine to comparable concentrations in young and old mice. In the euthyroid state, TH transporter expression was significantly higher in old than in young mice, except for Mct8 and Oatp1a1 expression levels. Hyperthyroidism resulted in upregulation of Mct10, Lat1 and Lat2 in liver tissue, while Oatp1a1, Oatp1b2 and Oatp1a4 expression was downregulated. This effect was preserved in old animals. Conclusion: Here, we show age-dependent differences in TH transporter mRNA expression in the euthyroid and hyperthyroid state of mice focusing on the liver as a classical TH target organ

The effect of high dose isoflavone supplementation on serum reverse T3 in euthyroid men with Type 2 Diabetes and post-menopausal women

Background: The health benefits of soy are widely reported but there are queries on the effect of soy isoflavones on thyroid function and the underlying mechanism of action.Materials and Methods: We examined the effect of soy isoflavones on reverse tri-iodothyronine (or 3,3′,5′-tri-iodothyronine; rT3) in two studies comprising 400 patients: 200 men (study 1; 3 months) and 200 post-menopausal women (study 2; 6 months) who were randomized to consume 15 g soy protein with 66 mg of isoflavones (SPI) daily, or 15 g soy protein alone without isoflavones (SP) daily.Results: SPI supplementation increased rT3 serum concentration in both men 0.41 (0.12) vs. 0.45 (0.14) nmol/L and women 0.33 (0.12) vs. 0.37 (0.09) nmol/L at 3 months compared to SP that was not seen at 6 months. Thyroid stimulating hormone (TSH) serum concentrations increased while free thyroxine (fT4) concentrations decreased with 3 months of SPI compared to SP supplementation for both men and women. rT3 correlated with TSH in both studies (p = 0.03) but not with either fT3 or fT4. fT3 levels did not differ between the SPI and SP preparations.Conclusion: Soy isoflavones transiently increased rT3 levels within 3 months though reverted to baseline at 6 months. The mechanism for this would be either rT3 degrading deiodinase 1 and/or deiodinase 2 activities are transiently inhibited at 3 months, or inhibition of deiodinase 3, which generates rT3 from T4 is induced at 6 months. These changes were mirrored in the TSH concentrations, suggesting that short-term high dose isoflavone transiently impairs thyroid function in the first 3 months and may impact on general health during this period

Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

Context: 3,5-Diiodo-L-thyronine (3,5-T2) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by a high-fat diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T2 and glucose but not lipid metabolism. Objective: The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T2 concentrations in healthy individuals. Study Design and Methods: Urine metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by 1H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T2 concentrations. Results: Serum 3,5-T2 concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T2 concentrations doubled owing to a 1-standard deviation (SD) decrease in urine trigonelline levels, or increased by 29-50% in relation to a 1-SD decrease in urine pyroglutamate, acetone and hippurate levels. Conclusion: Our findings in humans confirmed the metabolic effects of circulating 3,5-T2 on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T2 exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones

Sex-specific phenotypes of hyperthyroidism and hypothyroidism in mice

Background Thyroid dysfunction is more common in the female population, however, the impact of sex on disease characteristics has rarely been addressed. Using a murine model, we asked whether sex has an influence on phenotypes, thyroid hormone status, and thyroid hormone tissue response in hyper- and hypothyroidism. Methods Hypo- and hyperthyroidism were induced in 5 -month-old female and male wildtype C57BL/6N mice, by LoI/MMI/ClO4 − or T4 i.p. treatment over 7 weeks, and control animals underwent sham treatment (N = 8 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination, and strength), liver function, serum thyroid hormone status, and cellular TH effects on gene expression in brown adipose tissue, heart, and liver. Results Male and female mice showed significant differences in behavioural, functional, metabolic, biochemical, and molecular traits of hyper- and hypothyroidism. Hyperthyroidism resulted in increased locomotor activity in female mice but decreased muscle strength and motor coordination preferably in male animals. Hypothyroidism led to increased water intake in male but not female mice and significantly higher serum cholesterol in male mice. Natural sex differences in body temperature, body weight gain, food and water intake were preserved under hyperthyroid conditions. In contrast, natural sex differences in heart rate disappeared with TH excess and deprivation. The variations of hyper- or hypothyroid traits of male and female mice were not explained by classical T3/T4 serum state. TH serum concentrations were significantly increased in female mice under hyperthyroidism, but no sex differences were found under eu- or hypothyroid conditions. Interestingly, analysis of expression of TH target genes and TH transporters revealed little sex dependency in heart, while sex differences in target genes were present in liver and brown adipose tissue in line with altered functional and metabolic traits of hyper- and hypothyroidism. Conclusions These data demonstrate that the phenotypes of hypo- and hyperthyroidism differ between male and female mice and indicate that sex is an important modifier of phenotypic manifestations