Thyroid hormones has its main role in controlling metabolism, but it can also modulate extracellular fluid Volume (ECFV) through its action on the expression and activity of Na(+) transporters. Otherwise, chloride is the main anion in the ECFV and the influence of thyroid hormones in the regulation of chloride transporters is not yet understood. In this work, we studied the effect of thyroid hormones in the expression of ClC-2, a cell Volume-, pH- and voltage-sensitive Cl(-) channel, in rat kidney. To analyze the modulation of ClC-2 gene expression by thyroid hormones, we used hypothyroid (Hypo) rats with or without thyroxine (T(4)) replacement and hyperthyroid (Hyper) rats as our experimental models. Total RNA was isolated and the expression of ClC-2 mRNA was evaluated by a ribonuclease protection assay, and/or semi-quantitative RT-PCR. Renal ClC-2 expression decreased in Hypo rats and increased in Hyper rats. In addition, semi-quantitative RT-PCR of different nephron segments showed that these changes were due exclusively to the modulation of ClC-2 mRNA expression by thyroid hormone in convoluted and straight proximal tubules. To investigate whether thyroid hormones action was direct or indirect, renal proximal tubule primary culture cells were prepared and subjected to different T(4) concentrations. ClC-2 mRNA expression was increased by T(4) in a dose-dependent fashion, as analyzed by RT-PCR. Western blotting demonstrated that ClC-2 protein expression followed the same profile of mRNA expression.
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- Abstract: Thyroid* x
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- Abstract: TSHR x
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D Santos Ornellas, R Grozovsky, RC Goldenberg, DP Carvalho, P Fong, WB Guggino and M Morales
ST Chen, HY Shieh, JD Lin, KS Chang and KH Lin
To correlate the differentiation phenotype of two human thyroid cancer cell lines with their expression of various molecular markers, we analyzed the mRNA levels of four thyroid-specific genes, including thyrotropin receptor (TSHR), thyroglobulin (Tg), thyroid transcription factor-1 (TTF-1), and paired-box containing transcription factor-8 (PAX-8) genes. The results showed a differentiation-status-related pattern in which a well-differentiated cell line (WRO) expressed all the four genes, in contrast to an anaplastic cell line (ARO) that expressed TTF-1 and reduced levels of TSHR, but no Tg or PAX-8 genes. Furthermore, to verify the finding of concomitant loss of beta subtype thyroid hormone receptor (TRbeta) and TSHR gene expression in neoplastic thyroid tumors (Bronnegard et al. 1994), we examined the expression levels of TRbeta1 gene in these cell lines. Whereas the WRO cells produced an abundant amount of TRbeta1 protein detectable by immunoprecipitation, the ARO cells produced none. This new observation prompted us to investigate whether overexpression of TRbeta1 protein in ARO cells might produce changes in the differentiation phenotypes. We found that the level of expression of the TSHR gene and the proliferative index of ARO cells were significantly upregulated in the cells stably transfected with wild-type TRbeta1. These findings suggest that TRbeta1 protein overexpression can affect the differentiation phenotypes and induce more efficient cell proliferation of the anaplastic ARO cells.
Anne H van der Spek, Eric Fliers and Anita Boelen
Thyroid hormone (TH) metabolism and thyroid status have been linked to various aspects of the immune response. There is extensive literature available on the effects of thyroid hormone on innate immune cells. However, only recently have authors begun to study the mechanisms behind these effects and the role of intracellular TH metabolism in innate immune cell function during inflammation. This review provides an overview of the molecular machinery of intracellular TH metabolism present in neutrophils, macrophages and dendritic cells and the role and effects of intracellular TH metabolism in these cells. Circulating TH levels have a profound effect on neutrophil, macrophage and dendritic cell function. In general, increased TH levels result in an amplification of the pro-inflammatory response of these cells. The mechanisms behind these effects include both genomic and non-genomic effects of TH. Besides a pro-inflammatory effect induced by extracellular TH, the cellular response to pro-inflammatory stimuli appears to be dependent on functional intracellular TH metabolism. This is illustrated by the fact that the deiodinase enzymes and in some cell types also thyroid hormone receptors appear to be crucial for adequate innate immune cell function. This overview of the literature suggests that TH metabolism plays an important role in the host defence against infection through the modulation of innate immune cell function.
R. McG. HARDEN, M. T. HARRISON, W. D. ALEXANDER and B. E. C. NORDIN
Certain aspects of calcium and phosphorus metabolism have been studied in thirty-six patients with thyrotoxicosis.
The plasma calcium and inorganic phosphorus concentrations were not significantly different from normal.
The basal phosphate excretion index was low (− 0·08 ± 0·01) and there was an impaired response to high phosphate feeding.
These findings suggest that parathyroid function is reduced in thyrotoxicosis.
M L Panno, E Beraldi, V Pezzi, M Salerno, G De Luca, M Lanzino, M Le Pera, D Sisci, M Prati, S Palmero, E Bolla, E Fugassa and S Andò
The aim of the present study was to investigate the influence of thyroid hormones on androgen metabolism in Sertoli cells isolated from 3- and 4- week-old rats.
Hypothyroidism was induced by the oral administration of 0·025% methimazole (MMI) from birth until the rats were killed at 3 and 4 weeks of age. Half of the MMI-treated animals were injected i.p. with l-tri-iodothyronine (T3 3 μg/100 g body weight) during the last week before death. Sertoli cells from all groups were initially cultured under basal conditions for the first 24 h and subsequently in the presence of testosterone with or without T3 for an additional 24 h. Hypothyroidism was associated with severe impairment of body as well as testicular growth. Indeed, body and testicular weights were similar in 4-week-old hypothyroid animals to those in 3-week-old control rats.
Testosterone metabolism in Sertoli cells isolated from 3- and 4-week-old hypothyroid rats was mainly expressed by the lowering of 5α-dihydrotestosterone + androstane 3α, 17β–diol and an enhanced formation of 5α-reduced steroids with poor androgenic properties (e.g. 5α–androstane, 3, 17α-dione (androstanedione), 5α–androstan, 3-ol-17-one (androsterone)). Treatment of the same group of animals with T3 in vivo and in vitro did not influence the pattern of 5α–reductase steroids substantially.
The most striking finding in the Sertoli cells of 3-week-old hypothyroid rats was the dramatic enhancement of oestradiol formation which persisted to a lesser extent 1 week later. Oestradiol formation was greatly decreased by the addition of T3 in vivo and in vitro in hypothyroid animals.
These results suggest that T3 might influence androgen metabolism during the functional maturation of Sertoli cells.
Journal of Endocrinology (1994) 140, 349–355
1. The effect of 250 μg./day stilboestrol on thyroid hormone metabolism in sheep has been investigated.
2. After 5 days the conversion ratio was significantly increased and the rate of release of iodine from the thyroid also rose.
3. After 40 days the thyroxine utilization rate increased but the turnover rate was reduced. This effect was presumably due to a coincident increase in the plasma protein-bound iodine and the thyroxine distribution space.
4. It is suggested that small doses of oestrogen decrease tissue metabolism, inducing increased activity of the thyroid gland and a compensatory increase in the peripheral utilization of thyroid hormone.
ASHA CHANDOLA, D. SURESH KUMAR and J. P. THAPLIYAL
Thyroidectomy and orchidectomy led to significant reduction in the oxidative metabolism of isolated liver and skeletal muscle tissue (at 30 °C) in Calotes versicolor. Thyroxine and male hormone were shown to increase this parameter in intact and orchidectomized lizards respectively. The effects of thyroidectomy and orchidectomy on tissue oxygen uptake were not additive. It is supposed that by its effect on oxidative metabolism male hormone may be of a greater physiological importance for reptiles than for other vertebrates.
The present results show also that changes in environmental temperature can counteract the depressive effect of orchidectomy on the thyroid of this species of lizard.
Min Lu and Reigh-Yi Lin
Although TSH is the main regulator of thyroid growth and function, TSH binding activity in fat has long been reported. Since the TSH receptor (TSHR) has been detected in both preadipocytes and adipocytes, we hypothesized that it may play a role in adipose differentiation. Here, we use an in vitro model of adipogenesis from mouse embryonic stem (ES) cells to define TSH function. Directed differentiation of ES cells into the adipose lineage can be achieved over a 3-week period. Although adipocyte differentiation is initiated early in the development of cultured ES cells, TSHR up-regulation is precisely correlated with terminal differentiation of those adipocytes. The adipocytes express TSHR on the cell surface and respond to TSH with increased intracellular cAMP production, suggesting the activation of the protein kinase A signaling pathway. To determine whether TSH impacts adipogenesis, we examined how adipocytes responded to TSH at various points during their differentiation from cultured ES cells. We found that TSH greatly increases adipogenesis when added in the presence of adipogenic factors. More importantly, our data suggest that TSH also stimulates adipogenesis in cultured ES cells even in the absence of adipogenic factors. This finding provides the first evidence of TSH being a pro-adipogenic factor that converts ES cells into adipocytes. It further highlights the potential of ES cells as a model system for use in the study of TSH's role in the regulation of physiologically relevant adipose tissue.
A Boelen, J Kwakkel, DC Thijssen-Timmer, A Alkemade, E Fliers and WM Wiersinga
During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T(3)) and thyroxine (T(4)) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus-pituitary-thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the time-course of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS).LPS rapidly induced interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-beta2, TSHbeta and 5'-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TRbeta1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T(3) and T(4) fell only after 24 h.Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.
I. M. D. JACKSON, C. R. M. PRENTICE and MARGARET T. McKIDDIE
Although the clinical association of hypothyroidism and diabetes mellitus is well known (Phair, Bondy & Abelson, 1965; Hecht & Gershberg, 1968) there have been few studies of glucose and insulin metabolism in hypothyroidism before and after treatment; this paper reports our findings in ten such subjects.
Ten patients (9 female, 1 male; aged 43–73 yr.) with obvious clinical hypothyroidism, due to primary thyroid failure confirmed by a combination of serum protein-bound iodine, radioactive iodine studies with thyroid-stimulating hormone stimulation (as appropriate) and thyroid antibody studies, were investigated. None were known to be diabetic. An oral glucose tolerance test (50 g.) before and after treatment was performed, venous blood being removed for determination of blood sugar and plasma insulin levels at 0, 30, 60, 90 and 120 min. The sugar was measured as total reducing substances in a Technicon auto-analyser and plasma insulin by the double antibody radioimmunoassay method of Hales