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Local Control of Thyroid Hormone Action

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 23745

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Prof. Dr. Heike Heuer

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Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Universitätsklinikum Essen, Hufelandstr. 55, D-45147 Essen, Germany
Interests: Thyroid hormone transport and action in health and disease
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Thyroid hormones (TH) regulate many cellular processes, including proliferation, differentiation, and mitochondrial activity. Thus, proper TH signaling is critical for the homeostasis of almost all tissues and essential for normal brain development. According to the classical view, cell-specific TH action is largely determined by circulating TH concentrations that, in turn, are predominantly regulated by the activity of the hypothalamus–pituitary–thyroid axis. The discovery of different (1) TH transporters facilitating TH access to target cells, (2) deiodinases activating or inactivating TH intracellularly, as well as (3) distinct TH receptors and modes of intracellular receptor signaling has challenged this view and has shifted the focus from systemic TH levels toward the molecular components controlling local TH action. A broader understanding of TH transporters, deiodinase, receptors and their (patho-)physiological regulation will shed light on the molecular mechanisms underlying rare as well as common diseases with distinct changes in local TH homeostasis. Such knowledge will pave the ground for the development of pharmacological tools that may ultimately result in novel therapeutic approaches by modulating TH signaling in a cell-specific manner.

This Special Issue of the International Journal of Molecular Sciences focuses on TH transporters, deiodinases, and TH receptors and welcomes both original research articles and reviews that address molecular mechanisms underlying local control of TH signaling in health and disease.

Prof. Dr. Heike Heuer
Guest Editor

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Keywords

TH receptors
Deiodinases
TH transporters
Canonical/noncanonical signaling
TH metabolism
Pathophysiology
Animal model
hiPSC

Related Special Issue

Local Control of Thyroid Hormone Action 2.0 in International Journal of Molecular Sciences (3 articles)

Published Papers (12 papers)

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Research

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16 pages, 2834 KiB

Open AccessArticle

Triac Treatment Prevents Neurodevelopmental and Locomotor Impairments in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

by Jiesi Chen, Eva Salveridou, Lutz Liebmann, Sivaraj M. Sundaram, Denica Doycheva, Boyka Markova, Christian A. Hübner, Anita Boelen, W. Edward Visser, Heike Heuer and Steffen Mayerl

Int. J. Mol. Sci. 2023, 24(4), 3452; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043452 - 09 Feb 2023

Cited by 2 | Viewed by 1875

Abstract

Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to compromised central TH transport and action. As a therapeutic strategy, application of thyromimetic, MCT8-independent compounds Triac (3,5,3′-triiodothyroacetic acid), and Ditpa (3,5-diiodo-thyropropionic acid) was proposed. Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency. Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks. Saline-injected Wt and Dko mice served as controls. A second cohort of Dko mice received Triac (400 ng/g) daily between postnatal weeks 3 and 6. Thyromimetic effects were assessed at different postnatal stages by immunofluorescence, ISH, qPCR, electrophysiological recordings, and behavior tests. Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks. Ditpa (4000 ng/g) application to Dko mice during the first three postnatal weeks resulted in normal myelination and cerebellar development but only mildly improved neuronal parameters and locomotor function. Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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33 pages, 36427 KiB

Open AccessArticle

Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain

by Yu Wang, Ting Wang, Ana Montero-Pedrazuela, Ana Guadaño-Ferraz and Estrella Rausell

Int. J. Mol. Sci. 2023, 24(4), 3207; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043207 - 06 Feb 2023

Cited by 7 | Viewed by 2152

Abstract

Monocarboxylate transporter 8 (MCT8) and organic anion transporter polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters that play an important role in the availability of TH for neural cells, allowing their proper development and function. It is important to define which cortical cellular subpopulations express those transporters to explain why MCT8 and OATP1C1 deficiency in humans leads to dramatic alterations in the motor system. By means of immunohistochemistry and double/multiple labeling immunofluorescence in adult human and monkey motor cortices, we demonstrate the presence of both transporters in long-projection pyramidal neurons and in several types of short-projection GABAergic interneurons in both species, suggesting a critical position of these transporters for modulating the efferent motor system. MCT8 is present at the neurovascular unit, but OATP1C1 is only present in some of the large vessels. Both transporters are expressed in astrocytes. OATP1C1 was unexpectedly found, only in the human motor cortex, inside the Corpora amylacea complexes, aggregates linked to substance evacuation towards the subpial system. On the basis of our findings, we propose an etiopathogenic model that emphasizes these transporters’ role in controlling excitatory/inhibitory motor cortex circuits in order to understand some of the severe motor disturbances observed in TH transporter deficiency syndromes. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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19 pages, 6229 KiB

Open AccessArticle

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

by Jonathan Rochus Reinwald, Wolfgang Weber-Fahr, Alejandro Cosa-Linan, Robert Becker, Markus Sack, Claudia Falfan-Melgoza, Natalia Gass, Urs Braun, Christian Clemm von Hohenberg, Jiesi Chen, Steffen Mayerl, Thomas F. Muente, Heike Heuer and Alexander Sartorius

Int. J. Mol. Sci. 2022, 23(24), 15547; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415547 - 08 Dec 2022

Cited by 5 | Viewed by 1440

Abstract

Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout mice lacking MCT8 and organic anion transporting protein OATP1C1 (Mct8/Oatp1c1 DKO). In this study, we characterize impairments of brain structure and function in Mct8/Oatp1c1 DKO mice using multimodal magnetic resonance imaging (MRI) and assess the potential of the TH analogue 3,3′,5-triiodothyroacetic acid (TRIAC) to rescue this phenotype. Structural and functional MRI were performed in 11-weeks-old male Mct8/Oatp1c1 DKO mice (N = 10), wild type controls (N = 7) and Mct8/Oatp1c1 DKO mice (N = 13) that were injected with TRIAC (400 ng/g bw s.c.) daily during the first three postnatal weeks. Grey and white matter volume were broadly reduced in Mct8/Oatp1c1 DKO mice. TRIAC treatment could significantly improve white matter thinning but did not affect grey matter loss. Network-based statistic showed a wide-spread increase of functional connectivity, while graph analysis revealed an impairment of small-worldness and whole-brain segregation in Mct8/Oatp1c1 DKO mice. Both functional deficits could be substantially ameliorated by TRIAC treatment. Our study demonstrates prominent structural and functional brain alterations in Mct8/Oatp1c1 DKO mice that may underlie the psychomotor deficiencies in AHDS. Additionally, we provide preclinical evidence that early-life TRIAC treatment improves white matter loss and brain network dysfunctions associated with TH transporter deficiency. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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16 pages, 2844 KiB

Open AccessArticle

Tetrabromobisphenol A and Diclazuril Evoke Tissue-Specific Changes of Thyroid Hormone Signaling in Male Thyroid Hormone Action Indicator Mice

by Richárd Sinkó, Kristóf Rada, Anna Kollár, Petra Mohácsik, Miklós Tenk, Csaba Fekete and Balázs Gereben

Int. J. Mol. Sci. 2022, 23(23), 14782; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314782 - 26 Nov 2022

Cited by 1 | Viewed by 1369

Abstract

Thyroid hormone (TH) signaling is a prerequisite of normal tissue function. Environmental pollutants with the potential to disrupt endocrine functions represent an emerging threat to human health and agricultural production. We used our Thyroid Hormone Action Indicator (THAI) mouse model to study the effects of tetrabromobisphenol A (TBBPA; 150 mg/bwkg/day orally for 6 days) and diclazuril (10.0 mg/bwkg/day orally for 5 days), a known and a potential hormone disruptor, respectively, on local TH economy. Tissue-specific changes of TH action were assessed in 90-day-old THAI mice by measuring the expression of a TH-responsive luciferase reporter in tissue samples and by in vivo imaging (14-day-long treatment accompanied with imaging on day 7, 14 and 21 from the first day of treatment) in live THAI mice. This was followed by promoter assays to elucidate the mechanism of the observed effects. TBBPA and diclazuril impacted TH action differently and tissue-specifically. TBBPA disrupted TH signaling in the bone and small intestine and impaired the global TH economy by decreasing the circulating free T4 levels. In the promoter assays, TBBPA showed a direct stimulatory effect on the hdio3 promoter, indicating a potential mechanism for silencing TH action. In contrast, diclazuril acted as a stimulator of TH action in the liver, skeletal muscle and brown adipose tissue without affecting the Hypothalamo-Pituitary-Thyroid axis. Our data demonstrate distinct and tissue-specific effects of TBBPA and diclazuril on local TH action and prove that the THAI mouse is a novel mammalian model to identify TH disruptors and their tissue-specific effects. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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12 pages, 1681 KiB

Open AccessArticle

Cell-Specific Transport and Thyroid Hormone Receptor Isoform Selectivity Account for Hepatocyte-Targeted Thyromimetic Action of MGL-3196

by Georg Sebastian Hönes, Ramona Gowry Sivakumar, Christoph Hoppe, Jörg König, Dagmar Führer and Lars Christian Moeller

Int. J. Mol. Sci. 2022, 23(22), 13714; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213714 - 08 Nov 2022

Cited by 5 | Viewed by 2109

Abstract

Thyroid hormones (THs) and TH receptor-beta (TRβ) reduce hepatic triglycerides, indicating a therapeutic potential for TH analogs in liver steatosis. To avoid adverse extrahepatic, especially TRα-mediated effects such as tachycardia and bone loss, TH analogs with combined TRβ and hepatocyte specificity are desired. MGL-3196 is a new TH analog that supposedly meets these criteria. Here, we characterize the thyromimetic potential of MGL-3196 in cell-based assays and address its cellular uptake requirements. We studied the contribution of liver-specific organic anion transporters (OATP)1B1 and 1B3 to MGL-3196 action. The TR isoform-specific efficacy of MGL-3196 compared with 3,5,3′-triiodothyronine (T₃) was determined with luciferase assays and gene expression analysis in OATP1B1 and OATP1B3 and TRα- or TRβ-expressing cells and in primary murine hepatocytes (PMHs) from wild-type and TRβ knockout mice. We measured the oxygen consumption rate to compare the effects of MGL-3196 and T₃ on mitochondrial respiration. We identified OATP1B1 as the primary transporter for MGL-3196. MGL-3196 had a high efficacy (90% that of T₃) in activating TRβ, while the activation of TRα was only 25%. The treatment of PMHs with T₃ and MGL-3196 at EC₅₀ resulted in a similar induction of Dio1 and repression of Serpina7. In HEK293 cells stably expressing OATP1B1, MGL-3196 had comparable effects on mitochondrial respiration as T₃. These data indicate that MGL-3196’s hepatic thyromimetic action, the basis for its therapeutic use, results from a combination of hepatocyte-specific transport by OATP1B1 and the selective activation of TRβ over TRα. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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16 pages, 2744 KiB

Open AccessArticle

Cardioprotection by Hypothyroidism Is Not Mediated by Favorable Hemodynamics—Role of Canonical Thyroid Hormone Receptor Alpha Signaling

by Janina Pape, Helena Kerp, Helmut R. Lieder, Daniela Geist, Georg Sebastian Hönes, Lars C. Moeller, Petra Kleinbongard and Dagmar Führer

Int. J. Mol. Sci. 2022, 23(21), 13340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113340 - 01 Nov 2022

Cited by 1 | Viewed by 1346

Abstract

Hypothyroidism has been shown to reduce infarct size in rats, but the underlying mechanisms are unclear. We used isolated pressure-constant perfused hearts of control, hypothyroid and hyperthyroid mice and measured infarct size, functional parameters and phosphorylation of key molecules in cardioprotective signaling with matched heart rate. Compared with controls, hypothyroidism was cardioprotective, while hyperthyroidism was detrimental with enlarged infarct size. Next, we asked how thyroid hormone receptor α (TRα) affects ischemia/reperfusion (IR) injury. Thus, canonical and noncanonical TRα signaling was investigated in the hearts of (i) mice lacking TRα (TRα⁰), (ii) with a mutation in TRα DNA-binding domain (TRα^GS) and (iii) in hyperthyroid TRα⁰ (TRα⁰hyper) and TRα^GS mice (TRα^GShyper). TRα⁰ mouse hearts were protected against IR injury. Furthermore, infarct size was reduced in the hearts of TRα^GS mice that lack canonical TRα signaling but maintain noncanonical TRα action. Hyperthyroidism did not increase infarct size in TRα⁰ and TRα^GS mouse hearts. These cardioprotective effects were not associated with increased phosphorylation of key proteins of RISK, SAFE and eNOS pathways. In summary, chronic hypothyroidism and the lack of canonical TRα signaling are cardioprotective in IR injury and protection is not due to favorable changes in hemodynamics. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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15 pages, 29783 KiB

Open AccessArticle

Hepatobiliary Thyroid Hormone Deficiency Impacts Bile Acid Hydrophilicity and Aquaporins in Cholestatic C57BL/6J Mice

by Irina Kube, Manuela Kowalczyk, Ute Hofmann, Ahmed Ghallab, Jan Georg Hengstler, Dagmar Führer and Denise Zwanziger

Int. J. Mol. Sci. 2022, 23(20), 12355; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012355 - 15 Oct 2022

Cited by 3 | Viewed by 1660

Abstract

Women are more prone to develop either hypothyroidism or cholesterol gallstones than men. However, a male predominance in cholesterol gallstones under hypothyroidism was reported. Recently, a novel pathogenic link between thyroid hormone (TH) deficiency and cholesterol gallstones has been described in male mice. Here, we investigate if TH deficiency impacts cholesterol gallstone formation in females by the same mechanism. Three-month-old C57BL/6J mice were randomly divided into a control, a TH deficient, a lithogenic, and a lithogenic + TH deficient group and diet-treated for two, four, and six weeks. Gallstone prevalence, liver function tests, bile composition, hepatic gene expression, and gallbladder aquaporin expression and localization were investigated. Cholesterol gallstones were observed in lithogenic + TH deficient but not lithogenic only female mice. Diminished hydrophilicity of primary bile acids due to decreased gene expression of hepatic detoxification phase II enzymes was observed. A sex-specific expression and localization of hepatobiliary aquaporins involved in transcellular water and glycerol permeability was observed under TH deficient and lithogenic conditions. TH deficiency promotes cholesterol gallstone formation in female C57BL/6J mice by the same mechanism as observed in males. However, cholesterol gallstone prevalence was lower in female than male C57BL/6J mice. Interestingly, the sex-specific expression and localization of hepatobiliary aquaporins could protect female C57BL/6J mice to cholestasis and could reduce biliary water transport in male C57BL/6J mice possibly contributing to the sex-dependent cholesterol gallstone prevalence under TH deficiency. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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20 pages, 4934 KiB

Open AccessArticle

Insights into the Mechanism of Human Deiodinase 1

by Alfonso Rodriguez-Ruiz, Doreen Braun, Simon Pflug, Alexander Brol, Marc Sylvester, Clemens Steegborn and Ulrich Schweizer

Int. J. Mol. Sci. 2022, 23(10), 5361; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105361 - 11 May 2022

Cited by 7 | Viewed by 1723

Abstract

The three isoenzymes of iodothyronine deiodinases (DIO1-3) are membrane-anchored homo-dimeric selenoproteins which share the thioredoxin-fold structure. Several questions regarding their catalytic mechanisms still remain open. Here, we addressed the roles of several cysteines which are conserved among deiodinase isoenzymes and asked whether they may contribute to dimerization and reduction of the oxidized enzyme with physiological reductants. We also asked whether amino acids previously identified in DIO3 play the same role in DIO1. Human DIO1 and 2 were recombinantly expressed in insect cells with selenocysteine replaced with cysteine (DIO1^U126C) or in COS7 cells as selenoprotein. Enzyme activities were studied by radioactive deiodination assays with physiological reducing agents and recombinant proteins were characterized by mass spectrometry. Mutation of Cys124 in DIO1 prevented reduction by glutathione, while 20 mM dithiothreitol still regenerated the enzyme. Protein thiol reductants, thioredoxin and glutaredoxin, did not reduce DIO1^U126C. Mass spectrometry demonstrated the formation of an intracellular disulfide between the side-chains of Cys124 and Cys(Sec)126. We conclude that the proximal Cys124 forms a selenenyl-sulfide with the catalytic Sec126 during catalysis, which is the substrate of the physiological reductant glutathione. Mutagenesis studies support the idea of a proton-relay pathway from solvent to substrate that is shared between DIO1 and DIO3. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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14 pages, 2849 KiB

Open AccessArticle

Genetic and Neurological Deficiencies in the Visual System of mct8 Mutant Zebrafish

by Rotem Rozenblat, Adi Tovin, David Zada, Ilana Lebenthal-Loinger, Tali Lerer-Goldshtein and Lior Appelbaum

Int. J. Mol. Sci. 2022, 23(5), 2464; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052464 - 23 Feb 2022

Cited by 3 | Viewed by 2379

Abstract

Thyroid hormones (THs; T3 and T4) enter cells using specific transporters and regulate development and metabolism. Mutation in the TH transporter monocarboxylate transporter 8 (MCT8, SLC16A2) is associated with brain hypothyroidism and neurological impairment. We established mct8 mutant (mct8−/−) zebrafish as a model for MCT8 deficiency, which causes endocrinological, neurological, and behavioral alterations. Here, we profiled the transcriptome of mct8−/− larvae. Among hundreds of differentially expressed genes, the expression of a cluster of vision-related genes was distinct. Specifically, the expression of the opsin 1 medium wave sensitive 2 (opn1mw2) decreased in two mct8 mutants: mct8−/− and mct8^−25bp−/− larvae, and under pharmacological inhibition of TH production. Optokinetic reflex (OKR) assays showed a reduction in the number of conjugated eye movements, and live imaging of genetically encoded Ca²⁺ indicator revealed altered neuronal activity in the pretectum area of mct8^−25bp−/− larvae. These results imply that MCT8 and THs regulate the development of the visual system and suggest a mechanism to the deficiencies observed in the visual system of MCT8-deficiency patients. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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Review

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26 pages, 1142 KiB

Open AccessReview

Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System

by Joshua Seifert, Yingfu Chen, Wenzel Schöning, Knut Mai, Frank Tacke, Joachim Spranger, Josef Köhrle and Eva Katrin Wirth

Int. J. Mol. Sci. 2023, 24(5), 4861; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054861 - 02 Mar 2023

Cited by 6 | Viewed by 2688

Abstract

The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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18 pages, 5254 KiB

Open AccessReview

Thyroid Hormone Transporters in Pregnancy and Fetal Development

by Zhongli Chen, Marcel E. Meima, Robin P. Peeters and W. Edward Visser

Int. J. Mol. Sci. 2022, 23(23), 15113; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315113 - 01 Dec 2022

Cited by 6 | Viewed by 1940

Abstract

Thyroid hormone is essential for fetal (brain) development. Plasma membrane transporters control the intracellular bioavailability of thyroid hormone. In the past few decades, 15 human thyroid hormone transporters have been identified, and among them, mutations in monocarboxylate transporter (MCT)8 and organic anion transporting peptide (OATP)1C1 are associated with clinical phenotypes. Different animal and human models have been employed to unravel the (patho)-physiological role of thyroid hormone transporters. However, most studies on thyroid hormone transporters focus on postnatal development. This review summarizes the research on the thyroid hormone transporters in pregnancy and fetal development, including their substrate preference, expression and tissue distribution, and physiological and pathophysiological role in thyroid homeostasis and clinical disorders. As the fetus depends on the maternal thyroid hormone supply, especially during the first half of pregnancy, the review also elaborates on thyroid hormone transport across the human placental barrier. Future studies may reveal how the different transporters contribute to thyroid hormone homeostasis in fetal tissues to properly facilitate development. Employing state-of-the-art human models will enable a better understanding of their roles in thyroid hormone homeostasis. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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16 pages, 2485 KiB

Open AccessReview

TRα2—An Untuned Second Fiddle or Fine-Tuning Thyroid Hormone Action?

by Georg Sebastian Hönes, Nina Härting, Jens Mittag and Frank J. Kaiser

Int. J. Mol. Sci. 2022, 23(13), 6998; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23136998 - 23 Jun 2022

Cited by 2 | Viewed by 1955

Abstract

Thyroid hormones (THs) control a wide range of physiological functions essential for metabolism, growth, and differentiation. On a molecular level, TH action is exerted by nuclear receptors (TRs), which function as ligand-dependent transcription factors. Among several TR isoforms, the function of TRα2 remains poorly understood as it is a splice variant of TRα with an altered C-terminus that is unable to bind T3. This review highlights the molecular characteristics of TRα2, proposed mechanisms that regulate alternative splicing and indications pointing towards an antagonistic function of this TR isoform in vitro and in vivo. Moreover, remaining knowledge gaps and major challenges that complicate TRα2 characterization, as well as future strategies to fully uncover its physiological relevance, are discussed. Full article

(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)

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