Since TSH receptor (TSHR) expression increases during adipogenesis and signals via cAMP/phospho-cAMP-response element binding protein (CREB), reported to be necessary and sufficient for adipogenesis, we hypothesised that TSHR activation would induce preadipocyte differentiation. Retroviral vectors introduced constitutively active TSHR (TSHR*) into 3T3L1 preadipocytes; despite increased cAMP (RIA) and phospho-CREB (western blot) there was no spontaneous adipogenesis (assessed morphologically, using oil red O and QPCR measurement of adipogenesis markers). We speculated that Gβγ signalling may be inhibitory but failed to induce adipogenesis using activated Gsα (gsp*). Inhibition of phosphodiesterases did not promote adipogenesis in TSHR* or gsp* populations. Furthermore, differentiation induced by adipogenic medium with pioglitazone was reduced in TSHR* and abolished in gsp* expressing 3T3L1 cells. TSHR* and gsp* did not inactivate PPARγ (PPARG as listed in the HUGO database) by phosphorylation but expression of PPARγ1 was reduced and PPARγ2 undetectable in gsp*. FOXO1 phosphorylation (required to inactivate this repressor of adipogenesis) was lowest in gsp* despite the activation of AKT by phosphorylation. PROF is a mediator that facilitates FOXO1 phosphorylation by phospho-Akt. Its transcript levels remained constantly low in the gsp* population. In most measurements, the TSHR* cells were between the gsp* and control 3T3L1 preadipocytes. The enhanced down-regulation of PREF1 (adipogenesis inhibitor) permits retention of some adipogenic potential in the TSHR* population. We conclude that Gsα signalling impedes FOXO1 phosphorylation and thus inhibits PPARγ transcription and the alternative promoter usage required to generate PPARγ2, the fat-specific transcription factor necessary for adipogenesis.
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- Abstract: Thyroid* x
- Abstract: Digestion x
- Abstract: Thyroxine x
- Abstract: Thyroglobulin x
- Abstract: Thyroiditis x
- Abstract: Thyrotoxicosis x
- Abstract: Hypothyroidism x
- Abstract: Hyperthyroidism x
- Abstract: TSHR x
- Abstract: Metabolism x
Lei Zhang, Carol Paddon, Mark D Lewis, Fiona Grennan-Jones and Marian Ludgate
Camila Calvino, Luana L Souza, Ricardo H Costa-e-Sousa, Norma A S Almeida, Isis H Trevenzoli and Carmen C Pazos-Moura
Leptin has been shown to regulate the hypothalamus–pituitary–thyroid axis, acting primarily through the STAT3 pathway triggered through the binding of leptin to the long-chain isoform of the leptin receptor, ObRb. We previously demonstrated that although hyperthyroid rats presented leptin effects on TSH secretion, those effects were abolished in hypothyroid rats. We addressed the hypothesis that changes in the STAT3 pathway might explain the lack of TSH response to leptin in hypothyroidism by evaluating the protein content of components of leptin signalling via the STAT3 pathway in the hypothalamus and pituitary of hypothyroid (0.03% methimazole in the drinking water/21 days) and hyperthyroid (thyroxine 5 μg/100 g body weight /5 days) rats. Hypothyroid rats exhibited decreased ObRb and phosphorylated STAT3 (pSTAT3) protein in the hypothalamus, and in the pituitary gland they exhibited decreased ObRb, total STAT3, pSTAT3 and SOCS3 (P<0.05). Except for a modest decrease in pituitary STAT3, no other alterations were observed in hyperthyroid rats. Moreover, unlike euthyroid rats, the hypothyroid rats did not exhibit a reduction in food ingestion after a single injection of leptin (0.5 mg/kg body weight). Therefore, hypothyroidism decreased ObRb–STAT3 signalling in the hypothalamus and pituitary gland, which likely contributes to the loss of leptin action on food intake and TSH secretion, as previously observed in hypothyroid rats.
Milutin Milenkovic, Xavier De Deken, Ling Jin, Mario De Felice, Roberto Di Lauro, Jacques E Dumont, Bernard Corvilain and Francoise Miot
In the thyroid, H2O2 is produced at the apical pole of thyrocytes by one or two NADPH oxidases (NOX), Duox1/2 proteins. The onset of Duox expression was analysed by immunohistochemistry in the developing mouse thyroid in parallel with thyroglobulin (Tg) iodination and the expression of other thyroid differentiation markers. Duox proteins were found at embryonic day (E) 15.5 and were mainly localised at the apical pole of thyrocytes. Tg was detected 1 day before (E14.5) and Tg iodination was concomitant with the expression of both Duox and Na+/I− symporter (NIS; E15.5). The role of TSH in regulating Duox expression and H2O2 accumulation was evaluated in thyroids of adult mice with reduced (Tshr hyt/hyt or mice treated with thyroxine) or increased (methimazole or perchlorate treatment) TSH/Tshr activity. In mice with suppressed TSH/Tshr activity, Duox expression was only partially decreased when compared with wild-type, as observed by western blot. In Tshr hyt/hyt strain, Duox was still expressed at the apical pole and H2O2 measurements were normal. On the other hand, chronic TSH stimulation of the gland led to a decrease of H2O2 measurements without affecting Duox expression. The onset of Duox protein expression is compatible with their proposed function in thyroid hormone synthesis and it can be considered as a functional marker of the developing thyroid. However, Duox expression in adult is much less regulated by TSH than NIS and thyroperoxidase. It is not always correlated with the overall thyroid H2O2 accumulation, highlighting the importance of additional regulatory mechanisms which control either the production or H2O2 degradation.
C R Liu, L Y Li, F Shi, X Y Zang, Y M Liu, Y Sun and B H Kan
Thyroid dysfunction is classified into hyperthyroidism and congenital hypothyroidism (CH). Both hyperthyroidism and CH can cause heart lesions; however, the mechanisms involved remain unclear. The left ventricle was collected from eu-, hyper-, and hypothyroid rat. RNA was extracted and reverse-transcripted to cDNA. Real-time fluorescence quantitation-PCR was used to quantify the differential expression of thyroid hormone receptor (TR) subtype mRNA among eu-, hyper-, and hypothyroid rat myocardium. Here, we show that compared with the normal myocardium, TRα1 mRNA expression was upregulated by 51% (P<0.01), TRα2 mRNA expression was downregulated by 58% (P<0.01), and TRβ1 mRNA expression remained unchanged in hyperthyroid rat myocardium (P>0.05). TRα1, TRα2, and TRβ1 were expressed in normal and hypothyroid rat myocardium throughout the developmental process. In hypothyroid rats, myocardial TRα1 mRNA expression was generally downregulated and the expression peak appeared late. Myocardial TRα2 mRNA expression was generally upregulated and the expression peak appeared late. Myocardial TRβ1 mRNA expression was generally downregulated and changed similarly with the control group. In addition, the hypogenetic myocardium can be seen in the hypothyroid rat by pathology study. Taken together, the abnormal expression of TR subtype mRNA may have a close relationship with the pathogenesis of CH and hyperthyroidism heart disease.
J. Grinblat and A. Klein
A study was carried out to determine the effect on lymphocytic cortisol metabolism (LCM) of plasma from 62 patients with diffuse thyrotoxic goitre (DTG), 14 patients with toxic nodular goitre (TNG) and ten hypothyroid patients. Plasma of 33 healthy donors served as controls. A known concentration of human lymphocytes was incubated with cortisol in media containing 50% phosphate-buffered saline (PBS) and 50% of one of the following additions: (1) PBS, (2) homologous plasma (HP), (3) heterologous plasma, (4) plasma from DTG patients, (5) plasma from TNG patients, (6) plasma from hypothyroid patients, (7) PBS and HP to which l-thyroxine (T4) and tri-iodothyronine (T3) had been added separately and as a mixture up to a concentration ten times the normal, (8) boiled HP and (9) boiled DTG plasma. Plasma from hypothyroid patients gave an LCM-enhancing effect (LCMEE) similar to that of HP. The plasma of DTG and TNG patients had a markedly lesser effect on LCM than did HP. The T4 and T3 had no additional effect when added to PBS or HP. Boiling of HP and DTG plasma resulted in a similar decrease in LCMEE. The findings of this study raise the possibility of the existence of a factor inhibiting LCMEE in the plasma of thyrotoxic patients.
J. Endocr. 1984 101, 149–153
M Sahun, C Villabona, P Rosel, MA Navarro, JM Ramon, JM Gomez and J Soler
The aim of the present study was to study salt and water metabolism in thyroid deficiency. We performed an oral water loading test (OWL) and a hypertonic 5% saline infusion test (HSI) in 16 patients with overt primary hypothyroidism before replacement treatment (PRE group) and after, in eight patients with subclinical hypothyroidism (SUB group) and in 16 normal individuals (CG group). In the PRE group, a lower free water clearance was detected in the OWL (P < 0.022), with lower plasma osmolality (OWL: P < 0.005; HSI: P < 0.001) and arginine vasopressin (AVP) (OWL: P < 0.001; HSI: P < 0.001) than the CG group, across both tests; they normalized with the replacement treatment. The same plasma abnormalities were detected in the SUB group with the HSI. Although the AVP and thirst thresholds did not differ between the groups, the lag between them was lower in the PRE (4.1+/-3.2 mOsm/kg) and SUB group (2.6+/-2.1 mOsm/kg) than in the CG group (13.3+/-9.2 mOsm/kg) (P < 0.05). There were no differences in atrial natriuretic hormone (ANH), plasma renin activity (PRA) and plasma aldosterone among the groups. These results indicate that plasma hypo-osmolality and low levels of AVP are present in primary hypothyroidism, and indeed are already present in the subclinical phase of the disease. An overlap between the thresholds of thirst and AVP seem to play a role in these abnormalities, but ANH, PRA and plasma aldosterone do not appear to contribute.
S Van der Geyten, N Byamungu, G E Reyns, E R Kühn and V M Darras
Thyroid status is one of the most potent regulators of peripheral thyroid hormone metabolism in vertebrates. Despite this, the few papers that have been published concerning the role of thyroid hormones in the regulation of thyroid function in fish often offer conflicting data. We therefore set out to investigate the effects of tetraiodothyronine (thyroxine) (T4) or tri-iodothyronine (T3) supplementation (48 p.p.m.) via the food on plasma and tissue thyroid hormone levels as well as iodothyronine deiodinase (D) activities in the Nile tilapia (Oreochromis niloticus). T4 supplementation did not induce a hyperthyroid state and subsequently had no effects on the thyroid hormone parameters measured, with the liver as the sole notable exception. In T4-fed tilapias, the hepatic T4 levels increased substantially, and this was accompanied by an increase in in vitro type I deiodinase (D1) activity. Although the lack of effect of T4 supplementation could be partially explained by an inefficient uptake of T4 from the gut, our current data suggest that also the increased conversion of T4 into reverse (r)T3 by the D1 present in the liver plays an important role in this respect. In addition, T3 supplementation increased plasma T3 and decreased plasma T4 concentrations. T3 levels were also increased in the liver, brain, kidney, gill and white muscle, but without affecting local T4 concentrations. However, this increase in T3 availability remained without effect on D1 activity in liver and kidney. This observation, together with the 6-n-propylthiouracyl (PTU) insensitivity of the D1 enzyme in fish, sets the D1 in teleost fish clearly apart from its mammalian and avian counterparts. The changes in hepatic deiodinases confirm the role of the liver as an important T3-regulating tissue. However, the very short plasma half-life of exogenously administered T3 implies the existence of an efficient T3 clearing/degradation mechanism other than deiodination.
Hidenori Nagao, Tetsuya Imazu, Hiroyuki Hayashi, Kenjo Takahashi and Kouichi Minato
Little is known about the kinetics and metabolism of thyroid hormones in the hypothyroid state. To investigate these factors, we developed a reliable method for measurement of serum thyroxine (T4), triiodothyronine (T3), reverse-T3 (rT3) and stable isotope-labeled T4 ([13C9]T4), using online solid-phase extraction liquid chromatography–mass spectrometry/mass spectrometry (online SPE LC–MS/MS). We measured supply and turnover rates of T4 in thyroidectomized (Tx) rats using [13C9]T4 as a tracer. In rats, serum T4, T3 and rT3 were decreased but not completely ablated after surgical Tx. Endogenous T4 and T3 levels in Tx rats were maintained at a constant low level throughout the experimental period. [13C9]T4 levels declined with a half-life of ∼1.2 days after it was administered to Tx rats intravenously. These findings strongly suggest that serum T4 levels in Tx rats are maintained by T4 supplied by extra-thyroidal tissues (e.g. secretion of extra-thyroidal storage, enhancement of enterohepatic recirculation, and production in extra-thyroidal tissues). Moreover, the turnover rate of T4 in Tx rats was approximately twofold lower than in controls. This finding suggests that degradation of serum T4 is repressed by Tx. In conclusion, serum T4 is maintained at a constant low level by T4 supply from extra-thyroidal tissues and repression of T4 degradation in Tx rats. The powerful online SPE LC–MS/MS tool can be used to investigate thyroid hormones kinetics and metabolism, and thus has the potential to be used as a diagnostic tool and to investigate the pathogenesis of thyroid disease.
M A L Costa da Veiga, K de Jesus Oliveira, F H Curty and C C Pazos de Moura
We investigated the influence of hypo- and hyperthyroidism on the ability of leptin to modulate TSH secretion. Two hours after receiving leptin (8 μg leptin/100 g BW; s.c.), hyperthyroid rats (10 μg thyroxine (T4)/100 g body weight (BW) for 5 days) showed a 1.7-fold increase in serum TSH (P<0.05); in hypothyroid rats, leptin had no effect. Hemi-pituitaries of hyperthyroid rats incubated with 10−9 and 10−7M leptin showed reductions in TSH release of 40 and 50% respectively (P<0.05); incubation with 1:2000 and 1:500 dilutions of antiserum against leptin resulted in 3- and 4-fold higher TSH release (P<0.05 and P<0.001 respectively). However, in hypothyroid pituitaries leptin or the antiserum had no effect. The results suggest that the in vivo and in vitro responsiveness of TSH to leptin is abolished in hypothyroidism and is preserved in short-term hyperthyroidism, in comparison to previous reports in euthyroidism. In addition, the inhibitory action of pituitary leptin is enhanced in hyperthyroid glands, which may suggest a role for locally produced leptin in the suppression of TSH release associated with hyperthyroidism.
B Bakker, T Vulsma, J de Randamie, AM Achterhuis, B Wiedijk, H Oosting, C Glas and JJ de Vijlder
We studied the effects of the presence or absence of the thyroid gland on the iodine metabolism and excretion in term Dutch newborns by performing a retrospective study of the urinary iodine excretion in 193 term newborns with abnormal congenital hypothyroidism screening results. Thirty-six euthyroid newborns with decreased thyroxine-binding globulin levels were compared with 157 hypothyroid patients, 54 due to thyroid agenesis and 103 due to thyroid dysgenesis. A significant difference in the urinary iodine excretion was observed between the agenesis group (mean: 28 micrograms/24 h) and the euthyroid newborns (mean: 46 micrograms/24 h, P=0.001). In conclusion, healthy, euthyroid, term newborns excreted more iodine in their urine than newborns with thyroid agenesis. These results strongly indicated the existence of a temporarily negative iodine balance: the excretion of iodine prevailed over the intake and the newborn's thyroidal iodine, stored during pregnancy, could be used for thyroxine synthesis in the postnatal period. Since healthy term neonates were able to maintain adequate plasma free thyroxine concentrations under normal TSH stimulation, the prenatally acquired iodine stores could be considered sufficiently high to compensate for the transient postnatal losses.