3,5-Di-iodo-l-thyronine suppresses TSH in rats in vivo and in rat pituitary fragments in vitro

Horst, C; Harneit, Angelika; Seitz, Hans; Rokos, Hartmut

doi:10.1677/joe.0.1450291

Cited by 29 publications

(27 citation statements)

References 17 publications

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“…However, we show that at in vivo doses of T 2 and T 3 resulting in equivalent induction of ME gene expression, T 2 is significantly less potent in suppressing plasma TSH. These data would suggest that, in vivo, although capable of suppressing TSH, T 2 does not have selective central thyromimetic activity, in fact being better at inducing hepatic ME gene expression than suppressing TSH (Horst et al 1995). The reasons for the discrepancy between the data from the present study and those from Horst et al are not clear.…”

Section: Discussioncontrasting

confidence: 88%

“…Previous data have indicated that T 2 is capable of suppressing plasma TSH at doses that do not produce significant peripheral effects and, moreover, have shown T 2 to have selective central effects relative to T 3 (Horst et al 1995). Our data confirm the selective thyromimetic activity of T 2 in vivo and in vitro.…”

Section: Discussionsupporting

confidence: 87%

“…However, it has recently been shown that T 2 is able to suppress thyroid-stimulating hormone (TSH) levels in vivo, at doses that do not produce significant peripheral manifestations of thyroid hormone activity (Horst et al 1995). Furthermore, when doses producing equivalent suppression of TSH were compared following long-term administration, T 2 produced significantly smaller changes in peripheral indices of thyroid hormone activity than did T 3 .…”

Section: Introductionmentioning

confidence: 99%

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3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro

Ball¹,

Sokolov²,

Ww³

1997

Journal of Molecular Endocrinology

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Recent data have suggested that the iodothyronine, 3,5-diiodo-l-thyronine (T 2 ), has selective thyromimetic activity. In vivo, T 2 has been shown to suppress TSH levels at doses that do not produce significant peripheral manifestations of thyroid hormone activity. Furthermore, T 2 has been shown to produce smaller increments in peripheral indices of thyroid status than does T 3 , when doses resulting in equivalent suppression of circulating TSH are compared. We have assessed the selective thyromimetic activity of T 2 in vivo and in vitro, and performed in vitro studies to assess the potential molecular basis for these selective properties. T 2 was 100-fold less potent than T 3 in stimulating GH mRNA levels in GH 3 cells. In contrast, the iodothyronines were almost equivalent in their ability to downregulate TR 2 mRNA levels in this cell line. Both 3,3 -diiodo--thyronine and thyronine exhibited no significant thyromimetic effects on either process. In vivo, doses of T 2 and T 3 that were equivalent in their induction of hepatic malic enzyme (ME) mRNA did not produce equivalent suppression of circulating TSH, with T 2 being only 27% as effective as T 3 . T 2 was up to 500-fold less potent than T 3 in displacing [125 I]-T 3 from in vitro translated specific nuclear receptors (TRs) and GH 3 cell nuclear extracts. Electrophoretic mobility shift assays, assessing the ability of T 2 to produce dissociation of TR 1 homodimers from inverted palindrome T 3 response elements, indicated that T 2 was also 1000-fold less potent than T 3 in this respect. These data confirm that T 2 has significant thyromimetic activity, and that this activity is selective both in vivo and in vitro. However, there are no data to support a selective central effect, T 2 being relatively more potent in stimulating hepatic ME mRNA than in suppression of TSH in vivo. The basis for this differential thyromimetic activity is not selective affinity of the different TR isoforms for T 2 , or divergent properties of T 2 in competitive binding and functional assays in vitro.

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Section: Discussioncontrasting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro

Ball¹,

Sokolov²,

Ww³

1997

Journal of Molecular Endocrinology

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“…In particular, this link is in accordance with animal studies showing that 3,5-T2 was only a third as potent as T3 in suppressing TSH concentrations, and rather high pharmacological 3,5-T2 concentrations are required for TSH suppression (34)(35)(36). However, several animal studies in rodents and other species, for example killifish, indicated that 3,5-T2 interferes with the hypothalamus-pituitary-thyroid axis at several levels such as pituitary, thyroid, and peripheral action, thereby displaying a broad spectrum of mechanisms involved such as classical interaction with TR and also rapid effects at the cell membrane and mitochondria (10,12,14,(34)(35)(36)(37)(38)(39)(40) (for a review, see (3)). Action of 3,5-T2 via these different targets and molecular mechanisms might occur at different 3,5-T2 concentrations and depend on acute or chronic exposure (35,37,40), thus possibly explaining the unexpected bell-shaped relationship with serum TSH.…”

Section: Discussionsupporting

confidence: 85%

Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2?

Pietzner

Lehmphul

Friedrich

et al. 2015

Thyroid

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Background: During the last two decades, it has become obvious that 3,5-diiodothyronine (3,5-T2), a wellknown endogenous metabolite of the thyroid hormones thyroxine (T4) or triiodothyronine (T3), not only represents a simple degradation intermediate of the former but also exhibits specific metabolic activities. Administration of 3,5-T2 to hypothyroid rodents rapidly stimulated their basal metabolic rate, prevented highfat diet-induced obesity as well as steatosis, and increased oxidation of long-chain fatty acids. Objective: The aim of the present study was to analyze associations between circulating 3,5-T2 in human serum and different epidemiological parameters, including age, sex, or smoking, as well as measures of anthropometry, glucose, and lipid metabolism. Methods: 3,5-T2 concentrations were measured by a recently developed immunoassay in sera of 761 euthyroid participants of the population-based Study of Health in Pomerania. Subsequently, analysis of variance and multivariate linear regression analysis were performed. Results: Serum 3,5-T2 concentrations exhibited a right-skewed distribution, resulting in a median serum concentration of 0.24 nM (1st quartile: 0.20 nM; 3rd quartile: 0.37 nM). Significant associations between 3,5-T2 and serum fasting glucose, thyrotropin (TSH), as well as leptin concentrations were detected ( p < 0.05). Interestingly, the association to leptin concentrations seemed to be mediated by TSH. Age, sex, smoking, and blood lipid profile parameters did not show significant associations with circulating 3,5-T2. Conclusion: Our findings from a healthy euthyroid population may point toward a physiological link between circulating 3,5-T2 and glucose metabolism.

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“…But in contrast to these beneficial effects, an undesired negative feedback inhibition of the hypothalamuspituitary-thyroid (HPT) axis accompanied by increased heart weight was observed at the dose effectively improving hepatic lipid metabolism and systemic lipid status (Jonas et al 2014). Such observations on doserelated thyromimetic actions, among others also on the pituitary and the heart, are in agreement with published results on mice and rats treated with 3,5-T 2 (Horst et al 1995, Goldberg et al 2012, Padron et al 2014.…”

Section: Introductionsupporting

confidence: 87%

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

Lietzow

Golchert

Homuth

et al. 2016

Journal of Molecular Endocrinology

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The endogenous thyroid hormone (TH) metabolite 3,5-diiodo-l-thyronine (3,5-T 2 ) acts as a metabolically active substance affecting whole-body energy metabolism and hepatic lipid handling in a desirable manner. Considering possible adverse effects regarding thyromimetic action of 3,5-T 2 treatment in rodents, the current literature remains largely controversial. To obtain further insights into molecular mechanisms and to identify novel target genes of 3,5-T 2 in liver, we performed a microarray-based liver tissue transcriptome analysis of male lean and diet-induced obese euthyroid mice treated for 4 weeks with a dose of 2.5 µg/g bw 3,5-T 2 . Our results revealed that 3,5-T 2 modulates the expression of genes encoding Phase I and Phase II enzymes as well as Phase III transporters, which play central roles in metabolism and detoxification of xenobiotics. Additionally, 3,5-T 2 changes the expression of TH responsive genes, suggesting a thyromimetic action of 3,5-T 2 in mouse liver. Interestingly, 3,5-T 2 in obese but not in lean mice influences the expression of genes relevant for cholesterol and steroid biosynthesis, suggesting a novel role of 3,5-T 2 in steroid metabolism of obese mice. We concluded that treatment with 3,5-T 2 in lean and diet-induced obese male mice alters the expression of genes encoding hepatic xenobiotic-metabolizing enzymes that play a substantial role in catabolism and inactivation of xenobiotics and TH and are also involved in hepatic steroid and lipid metabolism. The administration of this high dose of 3,5-T 2 might exert adverse hepatic effects. Accordingly, the conceivable use of 3,5-T 2 as pharmacological hypolipidemic agent should be considered with caution.3,5-T 2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

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3,5-Di-iodo-l-thyronine suppresses TSH in rats in vivo and in rat pituitary fragments in vitro

Cited by 29 publications

References 17 publications

3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro

3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro

Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2?

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

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