Administration of 3,5‐diiodothyronine (3,5‐T2) causes central hypothyroidism and stimulates thyroid‐sensitive tissues

Padrón, Álvaro; Louzada, Ruy A.; Pantaleão, Thiago U.; Santos, Maria Carolina de Souza dos; Araújo, Rutênio Luiz Castro de; Andrade, Bruno Geike de; Leandro, Monique da Silva; Werneck-de-Castro, João Pedro; Ferreira, Andrea Cláudia Freitas; Carvalho, Denise P.

doi:10.1530/joe-13-0502

Cited by 67 publications

(74 citation statements)

References 49 publications

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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: 86%

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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Section: Introductionsupporting

confidence: 86%

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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“…Our investigations were aimed at assessing the suppressive effects of this molecule on the pituitary-thyroid axis. 7 In line with the recent findings of Padron and colleagues, 6 our data show that the administration of 3,5-diiodo-L-thyronine to rats three times a week up to 4 weeks leads to a reduction in BW gain despite the decreased level of T4 and T3 serum levels. On the other hand, Lanni and colleagues 8 have shown that the administration of 25 mg/100 g of 3,5-T2 to rats may reduce BW gain and adiposity while no change in serum T4 levels was observed in animals fed a diet rich in fat and treat- ed with 3,5-T2.…”

Section: Discussionsupporting

confidence: 91%

“…The reduction in thyroid hormone levels may be secondary to the reduction in serum levels of TSH, which leads to a reduced activity and expression of sodium-iodide symporter (NIS), thyroid D1, and thyroid peroxidase (TPO). 6 These new data support the hypothesis that 3,5-T2 causes exogenous TSH suppression. Thus, 3,5-T2 may be used as a non-thyreomimetic pharmacological agent in the treatment of hypothyroidism.…”

Section: Discussionsupporting

confidence: 67%

“…5 On the basis of these observations we have performed some in vivo study to better define the effects of multiple administration of high doses of T2 on the onset of liver steatosis in rats fed diet rich in lipids and the influence of this treatment on TSH secretion as it has been earlier reported by Padron and colleauges. 6 N o n -c o m m e r c i a l u s e o n l y…”

Section: Introductionmentioning

confidence: 99%

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Effects of 3,5-diiodo-L-thyronine on the liver of high fat diet fed rats

Giammanco

Aiello

Casuccio³

et al. 2016

J Biol Res

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Experimental studies have highlighted that the administration of 3,5-diiodo-L-thyronine (T2) to rats fed diets rich in lipids induces a decrease of cholesterol and triglycerides plasma levels and body weight (BW) without inducing liver steatosis. On the basis of these observations we carried out some experimental in vivo studies to assess the effects of multiple high doses of T2 on the pituitary thyroid axis of rats fed diet rich in lipids. Fifteen male Wistar rats were divided into three groups of five animals each. The first group (N group) received standard diet, the second group was fed with a high fat diet (HFD group), while the third group (HFDT2 group) was additionally given T2 intraperitoneally at a dose level of 70 mg/100 g of BW three times a week up to four weeks. At the end of the treatment, blood sample from each animal was collected, centrifuged and the serum was stored at -20°C. The serum concentrations of thyroidstimulating hormone (TSH), triiodothyronine, thyroxine, adrenocorticotropic hormone, triglycerides, cholesterol, glucose, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase were then determined. In addition, liver of rats was examined by histology in order to assess the presence and degree of steatosis. The administration of T2 to rats fed with a high fat diet suppressed TSH secretion (P=0.013) while no steatosis was observed in the liver of these animals. Our data show that multiple administrations of high doses of T2 to rats fed diets rich in lipid inhibit TSH secretion and prevent the onset of liver steatosis in these animals.

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“…Also, stimulation of the cytochrome oxygenase was noted, but this data has not yet been independently confirmed. While only a few possible biological effects of 3,3′-T 2 and 3′,5′-T 2 have been reported, there is more information available for 3,5-T 2 , which circulates in human serum [26] and might rapidly and directly act on mitochondrial function and at higher concentrations also mimics T 3 effects via modulation of TR-dependent transcription in many target cells [27,28,29,30,31]. Moreover, it was recently demonstrated that 3,5-T 2 influences the volume of adipocytes by inducing lipolysis and increases the mitochondrial content in brown adipocytes and thermogenesis, thus demonstrating an influence of 3,5-T 2 on the metabolism [32].…”

Section: Discussionmentioning

confidence: 99%

Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3′-Diiodothyronine across the Plasma Membrane

Kinne¹,

Wittner²,

Wirth³

et al. 2015

Eur Thyroid J

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Thyroid hormones are transported across cell membranes by transmembrane transporter proteins, for example by members of the monocarboxylate transporter (MCT) and the L-type amino acid transporter (LAT) families. LATs consist of a light chain (e.g. LAT2) and a heavy chain (CD98), which is essential for their cell surface expression and functionality. The specificity of Lat2 for thyroid hormones and their metabolites and its role in their transport was not fully clear. This fact motivated us to establish a cell system to elucidate the uptake of thyroid hormones and their metabolites by mouse Lat2. The coinjection of cRNA coding for Lat2 and CD98 into Xenopus laevis oocytes resulted in a markedly increased level of 3,3′-diiodo-L-thyronine (3,3′-T₂) and to some extent also enhanced T₃ transport. To gain insight into properties of thyroid hormones and their metabolites transported by Lat2, we inhibited 3,3′-T₂ uptake by various iodothyronine derivatives. T₁ and T₂ derivatives as well as 2-aminobicyclo-[2,2,1]-heptane-2-carboxylic acid strongly competed with 3,3′-T₂ uptake. In addition, we performed T₂ uptake measurements with the thyroid hormone-specific transporter MCT8. For both Lat2 and MCT8, K_m values in a low micromolar range were calculated. We demonstrated that oocytes are a suitable system for thyroid hormone transport studies mediated by Lat2. Our data indicates that Lat2 compared to other thyroid hormone transporters prefers 3,3′-T₂ as the substrate. Thus, Lat2 might contribute to the availability of thyroid hormone by importing and/or exporting 3,3′-T₂, which is generated either by T₃ inactivation or by rapid deiodinase 1-mediated rT₃ degradation.

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Administration of 3,5‐diiodothyronine (3,5‐T2) causes central hypothyroidism and stimulates thyroid‐sensitive tissues

Cited by 67 publications

References 49 publications

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

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

Effects of 3,5-diiodo-L-thyronine on the liver of high fat diet fed rats

Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3′-Diiodothyronine across the Plasma Membrane

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