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Search for other papers by A I Korytko in
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Abstract
The GH-releasing hormone receptor (GHRH-R) is a critical link between hypothalamic GH-releasing hormone (GHRH) and pituitary GH secretion. However, the factors that regulate GHRH-R are not well understood. Despite the importance of thyroid hormone and glucocorticoids in influencing the GH axis in vivo, it is not known whether these hormones act directly at the pituitary to regulate expression of GHRH-R. We tested the effects of T3 and hydrocortisone on GHRH-R gene expression in primary pituitary cell cultures of adult male rats. Pituitary cells were treated for 24 h with increasing concentrations of T3 (0.06-60 nM) or hydrocortisone (2.8 nM-2.8 μM). GHRH-R mRNA levels were assessed by ribonuclease protection assay. T3 caused a striking dose-dependent increase in GHRH-R mRNA, reaching levels 5.1 ± 0.5 fold over controls (P<0·001). Hydrocortisone also stimulated a marked dose-dependent increase in GHRH-R mRNA, reaching levels 5.6 ± 0.7 fold over controls (P<0·001). Combined treatment with both hormones did not cause further augmentation of GHRH-R mRNA levels. These data indicate that T3 and hydrocortisone act directly at the pituitary as potent regulators of GHRH-R gene expression.
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Thyroid hormone (TH) action and metabolism require hormone transport across cell membranes. We have investigated the possibility that TH are substrates of amino acid transport (System L) mediated by heterodimers of 4F2 heavy-chain (hc) and the light-chain (lc) permease IU12. Co-expression of 4F2hc and IU12 cDNAs injected into Xenopus oocytes induces saturable, Na(+) -independent transport of tri-iodothyronine (T(3)), thyroxine (T(4)) (K(m) of 1.8 and 6.3 microM respectively), tryptophan and phenylalanine. Induced TH and tryptophan uptakes are inhibited by excess BCH (synthetic System L substrate). Induced TH uptake is also inhibited by excess reverse tri-iodothyronine (rT(3)), but not by triodothyroacetic acid (TRIAC) (TH analogue lacking anamino acid moiety). T(3) and tryptophan exhibit reciprocal inhibition of their 4F2hc-IU12 induced uptake. Transport pathways produced by 4F2hc-lc permease complexes may therefore be important routes for movement and exchange of TH (as well as amino acids) across vertebrate cell membranes, with a potential role in modulating TH action.
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Transport of thyroxine (T(4)) into the liver is inhibited in fasting and by bilirubin, a compound often accumulating in the serum of critically ill patients. We tested the effects of chronic and acute energy deprivation, bilirubin and its precursor biliverdin on the 15-min uptake of [(125)I]tri-iodothyronine ([(125)I]T(3)) and [(125)I]T(4) and on TSH release in rat anterior pituitary cells maintained in primary culture for 3 days. When cells were cultured and incubated in medium without glucose and glutamine to induce chronic energy deprivation, the ATP content was reduced by 45% (P<0. 05) and [(125)I]T(3) uptake by 13% (NS), but TSH release was unaltered. Preincubation (30 min) and incubation (15 min) with 10 microM oligomycin reduced ATP content by 51% (P<0.05) and 53% (P<0. 05) under energy-rich and energy-poor culture conditions respectively; [(125)I]T(3) uptake was reduced by 66% (P<0.05) and 64% (P<0.05). Neither bilirubin nor biliverdin (both 1-200 microM) affected uptake of [(125)I]T(3) or [(125)I]T(4). Bilirubin (1-50 microM) did not alter basal or TRH-induced TSH release. In conclusion, the absence of inhibitory effects of chronic energy deprivation and bilirubin on thyroid hormone uptake by pituitary cells supports the view that the transport is regulated differently than that in the liver.
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ABSTRACT
Rat liver nuclear thyroid hormone receptor lost 3,5,3′-tri-iodo-l-thyronine (T3)-binding activity with a half-life of 14 days, 4 h, 139 min, 62 min, 16 min or 6 min at 0, 36, 38, 40, 43 or 45 °C respectively, when present in crude nuclear extracts. Glycerol increased the half-life of the receptor during heat inactivation. Protection was reversible by removing the glycerol. The receptor was unstable at a pH below 6·0 or above 10·0. We also found a loss of the receptor activity during the separation of bound and free hormone using the resin test. Of several conditions tested for the separation of bound and free hormone, the addition of heated nuclear extract gave the most accurate estimation of bound hormone when using the resin test. Using these characteristics of the receptor, we purified the receptor to 1220 pmol T3-binding capacity/mg protein with a final yield of 14·6 μg/4 kg rat liver.
Journal of Endocrinology (1989) 120, 237–243
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Abstract
We have assessed the relative contribution of the thyroid hormones and noradrenaline (NA) on the calorigenic function of brown adipose tissue (BAT) as indicated by GDP binding and O2 consumption of BAT mitochondria. Male Wistar rats of 200 g body weight were made hypothyroid with 131I. Groups of animals were injected s.c., in divided doses, daily for 10 days, with thyroxine (2 μg/100 g body weight) or tri-iodothyronine (T3; 0·3 μg/100 g body weight). Animals were used 7 days after bilateral or unilateral sympathetic nerve excision of BAT (Sx). Sham-operated rats were used as controls. In normal rats kept at 22 °C, GDP binding reached 94 ± 24 pmol/mg protein; untreated hypothyroid rats had normal binding values whereas the T3-treated group showed an increased binding. Sx induced a sharp fall in the three groups (P<0·01). After 24-h exposure to 4 °C GDP binding increased in normal rats to about 410% (P<0·01) whereas binding failed to increase in response to cold in the untreated hypothyroid and the T3-treated groups. Sx reduced GDP binding in the three groups significantly (P<0·01). The consumption of O2 by BAT mitochondria showed similar variations in response to Sx and to cold exposure as did GDP binding. The data indicated that, at room temperature, BAT calorigenesis can function without the thyroid hormones, though not without the catecholamines. The findings in rats exposed to cold showed that the lack of NA was significantly more effective than the lack of thyroid hormones in preventing the BAT hyperactive response. This does not negate an active role for T3 in BAT calorigenesis.
Journal of Endocrinology (1995) 145, 579–584
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ABSTRACT
The effect of acute or chronic immunoneutralization of somatostatin (SRIF) on plasma GH, thyrotrophin (TSH) and thyroid hormones was examined. Acute responses to SRIF immunoneutralization were examined using 30 intact male lambs (19·8 ±0·6 kg) assigned to one of five treatment groups such that control (C) lambs received no anti-SRIF immunoglobulin and SRIF-immunized (SI) lambs received 2 mg (SI2), 10 mg (SI10), 20 mg (SI20) or 100 mg (SI100) anti-SRIF immunoglobulin/kg body weight (BW). Control immunoglobulin was administered such that all lambs received 100 mg total immunoglobulin protein/kg BW. Effects of chronic SRIF immunoneutralization were examined using C and SI100 lambs which received additional (40 mg/kg BW) control and anti-SRIF immunoglobulin respectively, 4 and 8 days following the initial dose. Blood samples were collected from all lambs, at 10-min intervals, for 5 h immediately following initial immunoglobulin infusion and, from C and SI100 lambs, at 10-min intervals, for 5 h at 11 days following initial immunoglobulin infusion. At the end of each 5-h sampling period, pituitary and thyroid function was examined by i.v. challenge with thyrotrophin-releasing hormone (TRH; 0·33 μg/kg BW). Basal plasma GH and thyroxine (T4) and the GH, TSH, T4 and tri-iodothyronine (T3) responses to TRH were not influenced by acute or chronic immunoneutralization of SRIF. Acute, but not chronic, immunoneutralization of SRIF elevated basal plasma T3 in SI100 lambs only. The results suggest that SRIF, under physiological conditions, does not influence GH or thyroid hormone secretion in sheep but may influence thyroid hormone metabolism acutely.
Journal of Endocrinology (1993) 136, 261–269
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ABSTRACT
In the present study the effects of insulin, glucocorticoids and thyroid hormones on macrophage metabolism and function were investigated. The maximum activities of hexokinase, glucose-6-phosphate dehydrogenase, glutaminase and citrate synthase were determined in macrophages obtained from hormonetreated rats and those cultured for a period of 48 h in the presence of hormones. Macrophage phagocytosis was markedly inhibited by dexamethasone and thyroid hormones, remaining unchanged when insulin was added to the culture medium, however. The changes in the enzyme activities caused by hormone treatments of the rats were very similar to those found in culture. Insulin enhanced citrate synthase and hexokinase activities and diminished those of glutaminase and glucose-6-phosphate dehydrogenase. Dexamethasone had a similar effect except on glucose6-phosphate dehydrogenase. The addition of thyroid hormones to the culture medium raised the activities of glutaminase and hexokinase and reduced that of citrate synthase. The results presented support the suggestion that the effects of insulin, glucocorticoids and thyroid hormones on immune and inflammatory responses could well be mediated through changes in macrophage metabolism..
Journal of Endocrinology (1992) 135, 213–219
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ABSTRACT
SR-202 is a non-iodinated potential lipid-altering agent. When administered (100 mg) three times per day for 3 days to six euthyroid subjects it was associated with a 30 ± 3% (mean ± s.e.m.) fall in 3,3′,5-tri-iodothyronine(T3)(P < 0·001), a reciprocal 104 ± 14% rise in 3,3′,5′-tri-iodothyronine (reverse T3, rT3) (P < 0·01), and a 37 ± 7% rise in thyroxine (T4) (P < 0·001). Basal and TRH-stimulated TSH did not change. These results suggested that SR-202 was acting as an inhibitor of the peripheral monodeiodination of T4 to T3.
During a second study the same subjects received the same dose of SR-202 for a further 3 days following 15 days of progressive substitutive treatment with l-T4, which they continued to take at 200 μg/day until the end of the study. Despite higher levels of thyroid hormones in the substituted subjects, similar results were observed, serum T3 falling by 40 ± 2% (P < 0·001), serum rT3 and T4 rising by 168 ± 24% (P < 0·01) and 37 ± 9% (P < 0·01) respectively. These changes provide compelling evidence that SR-202 is an inhibitor of the peripheral conversion of T4 to T3 that acts on thyroid hormone metabolism without provoking a counter-regulatory pituitary response. It might prove to be a useful tool for the clinical investigation of thyroid function.
J. Endocr. (1987) 112, 171–175
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SUMMARY
Intact mouse thyroid glands were used to measure the formation of cyclic [3H]AMP from [3H]adenine, and the release of thyroidal iodine. These two parameters of thyroid activity responded to similar concentrations of human thyroid-stimulating hormone (TSH). Both were stimulated by prostaglandin E1, although the response was always very much less than to TSH. Both were inhibited by NaF, which appeared to have a toxic effect on the gland. The response to TSH was in each case reduced by lithium, suggesting that the antithyroid effect of Li+ is associated with a direct action on adenyl cyclase; however, Li+ also reduced thyroidal hormone secretion induced by dibutyryl cyclic AMP and may therefore have a second site of action.
In general, the effects of these agents on cyclic [3H]AMP formation correlated well with their effects on thyroidal iodine release. The results support the hypothesis that the activation of adenyl cyclase is closely associated with, and precedes, thyroid hormone secretion.
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SUMMARY
Diced quarter anterior pituitaries from mature female Wistar rats were cultured in synthetic medium with or without added serum. Using each culture as its own control, the thyrotrophin-releasing hormone (TRH) dose–thyrotrophin (TSH) response characteristics of both media were similar; significant TSH secretion being stimulated at TRH doses around 1·5 × 10−9 mol/l. During days 1–3 of culture, basal TSH secretion fell significantly but TRH responsiveness was unchanged. Neither tri-iodothyronine (T3) nor thyroxine (T4) influenced basal TSH secretion.
In both culture media inhibition of TRH responsiveness was demonstrated with concentrations of T3 and T4 within the ranges 1·5 × 10−12 to 1·5 × 10−9 mol/l for T3 and 6·5 × 10−10 to 6·5 × 10−7 mol/l for T4. Equivalent inhibition was accompanied by similar T3 concentrations whether T3 or T4 supplements were used, suggesting that T4 itself has no feedback action. The similar concentrations of T3 required to inhibit TRH responsiveness in media either with or without serum suggest that the pituitary is responsive not only to free but also to total thyroid hormone concentrations, since serum-free medium contains no thyroid hormone-binding protein.