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SG Ball, J Sokolov, and WW Chin

Recent data have suggested that the iodothyronine, 3,5-diiodo-l-thyronine (T2), has selective thyromimetic activity. In vivo, T2 has been shown to suppress TSH levels at doses that do not produce significant peripheral manifestations of thyroid hormone activity. Furthermore, T2 has been shown to produce smaller increments in peripheral indices of thyroid status than does T3, when doses resulting in equivalent suppression of circulating TSH are compared. We have assessed the selective thyromimetic activity of T2 in vivo and in vitro, and performed in vitro studies to assess the potential molecular basis for these selective properties. T2 was 100-fold less potent than T3 in stimulating GH mRNA levels in GH3 cells. In contrast, the iodothyronines were almost equivalent in their ability to downregulate TRbeta2 mRNA levels in this cell line. Both 3,3'-diiodo-L-thyronine and thyronine exhibited no significant thyromimetic effects on either process. In vivo, doses of T2 and T3 that were equivalent in their induction of hepatic malic enzyme (ME) mRNA did not produce equivalent suppression of circulating TSH, with T2 being only 27% as effective as T3. T2 was up to 500-fold less potent than T3 in displacing [125I]-T3 from in vitro translated specific nuclear receptors (TRs) and GH3 cell nuclear extracts. Electrophoretic mobility shift assays, assessing the ability of T2 to produce dissociation of TRbeta1 homodimers from inverted palindrome T3 response elements, indicated that T2 was also 1000-fold less potent than T3 in this respect. These data confirm that T2 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, T2 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 T2, or divergent properties of T2 in competitive binding and functional assays in vitro.

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C Wrutniak-Cabello, F Casas, and G Cabello

Triiodothyronine (T3) is considered a major regulator of mitochondrial activity. In this review, we show evidence of the existence of a direct T3 mitochondrial pathway, and try to clarify the respective importance of the nuclear and mitochondrial pathways for organelle activity. Numerous studies have reported short-term and delayed T3 stimulation of mitochondrial oxygen consumption. Convincing data indicate that an early influence occurs through an extra-nuclear mechanism insensitive to inhibitors of protein synthesis. Although it has been shown that diiodothyronines could actually be T3 mediators of this short-term influence, the detection of specific T3-binding sites, probably corresponding to a 28 kDa c-Erb Aalpha1 protein of the inner membrane, also supports a direct T3 influence. The more delayed influence of thyroid hormone upon mitochondrial respiration probably results from mechanisms elicited at the nuclear level, including changes in phospholipid turnover and stimulation of uncoupling protein expression, leading to an increased inner membrane proton leak. However, the involvement of a direct mitochondrial T3 pathway leading to a rapid stimulation of mitochondrial protein synthesis has to be considered. Both pathways are obviously involved in the T3 stimulation of mitochondrial genome transcription. First, a 43 kDa c-Erb Aalpha1 protein located in the mitochondrial matrix (p43), acting as a potent T3-dependent transcription factor of the mitochondrial genome, induces early stimulation of organelle transcription. In addition, T3 increases mitochondrial TFA expression, a mitochondrial transcription factor encoded by a nuclear gene. Similarly, the stimulation of mitochondriogenesis by thyroid hormone probably involves both pathways. In particular, the c-erb Aalpha gene simultaneously encodes a nuclear and a mitochondrial T3 receptor (p43), thus ensuring coordination of the expression of the mitochondrial genome and of nuclear genes encoding mitochondrial proteins. Recent studies concerning the physiological importance of the direct mitochondrial T3 pathway involving p43 led to the conclusion that it is not only involved in the regulation of fuel metabolism, but also in the regulation of cell differentiation. As the processes leading to or resulting from differentiation are energy-consuming, p43 coordination of metabolism and differentiation could be of significant importance in the regulation of development.

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Yun-Qing Zhu, Yun Hu, Ke He, Na Li, Peng Jiang, Yu-Qin Pan, Hong Zhou, and Xiao-Ming Mao

of Tg required TSH simulation. We found that thyroid and peripheral blood Tregs all expressed TSH receptor and that thyroid Tregs expressed high levels of TSH receptor mRNA compared with peripheral blood Tregs ( Fig. 5A ) . As peripheral blood Tregs

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P Bargi-Souza, F Goulart-Silva, and M T Nunes

Nuclear thyroid receptors and the geneexpression regulation Most of the well-characterized actions of thyroid hormones (THs) are mediated by thyroid hormone receptors (THRs), the alpha (THRA) and beta (THRB) receptors, which belong to the

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Davide Calebiro, Viacheslav O Nikolaev, and Martin J Lohse

strict control of TSH, secreted by the anterior pituitary ( Magner 1990 ). TSH binds to a GPCR, the TSH receptor (TSHR), located on the basolateral membrane of thyroid epithelial cells ( Vassart & Dumont 1992 ). At physiological TSH concentrations, the

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Henrik Fagman and Mikael Nilsson

in FRS2α, a docking protein that links FGF receptor activation to downstream signaling pathways ( Kameda et al . 2009 ). It is thus conceivable that fetal thyroid size is determined both by the progenitor cell number generated while the primordium is

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Diego Russo, Giuseppe Damante, Efisio Puxeddu, Cosimo Durante, and Sebastiano Filetti

. 2007 , Seregni et al . 2009 , Middendorp & Grünwald 2010 ). Radioiodine uptake and concentration by transformed thyrocytes require the same machinery used for thyroid hormone synthesis, a process controlled by TSH receptor (TSHR) signaling and

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Gunnar Kleinau, Anne Müller, and Heike Biebermann

their functional properties in terms of β-arrestin recruitment ( Hanyaloglu et al . 2002 ). The secreted hormone thyrotropin (TSH), in turn, activates the thyroid gland via binding to the thyrotropin receptor (TSHR), which induces the production of

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Vaishnavi Venugopalan, Maren Rehders, Jonas Weber, Lisa Rodermund, Alaa Al-Hashimi, Tonia Bargmann, Janine Golchert, Vivien Reinecke, Georg Homuth, Uwe Völker, Francois Verrey, Janine Kirstein, Heike Heuer, Ulrich Schweizer, Doreen Braun, Eva K Wirth, and Klaudia Brix

Wirth Ek Schweizer U Heuer H Verrey F Brix K 2021b The amino acid transporter Mct10/Tat1 is important to maintain the TSH receptor at its canonical basolateral localization and assures regular turnover of thyroid follicle cells in male mice

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Ronald M Evans

Nuclear receptors (NRs) comprise a large family of signal dependent transcription factors that respond to a diverse range of fat soluble ligands including steroids, vitamins A and D, long chain fatty acids, bile acids, thyroid hormone and xenobiotic