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Endocrinology. 2018 Feb 1;159(2):1159-1171. doi: 10.1210/en.2017-00582.

A Transgenic Mouse Model for Detection of Tissue-Specific Thyroid Hormone Action.

Author information

1
Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
2
János Szentágothai PhD School of Neurosciences, Semmelweis University, Budapest, Hungary.
3
Medical Gene Technology Unit, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
4
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
5
Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Centre for Neuroscience, Pécs, Hungary.
6
Molecular Pharmacology Research Team, János Szentágothai Research Centre, Pécs, Hungary.
7
Second Department of Pediatrics, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
8
Hungarian Academy of Sciences-University of Pécs, Hungarian Brain Research Program, Chronic Pain Research Group, University of Pécs Medical School, Pécs, Hungary.
9
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts.
10
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts.
11
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois.

Abstract

Thyroid hormone (TH) is present in the systemic circulation and thus should affect all cells similarly in the body. However, tissues have a complex machinery that allows tissue-specific optimization of local TH action that calls for the assessment of TH action in a tissue-specific manner. Here, we report the creation of a TH action indicator (THAI) mouse model to study tissue-specific TH action. The model uses a firefly luciferase reporter readout in the context of an intact transcriptional apparatus and all elements of TH metabolism and transport and signaling. The THAI mouse allows the assessment of the changes of TH signaling in tissue samples or in live animals using bioluminescence, both in hypothyroidism and hyperthyroidism. Beyond pharmacologically manipulated TH levels, the THAI mouse is sufficiently sensitive to detect deiodinase-mediated changes of TH action in the interscapular brown adipose tissue (BAT) that preserves thermal homeostasis during cold stress. The model revealed that in contrast to the cold-induced changes of TH action in the BAT, the TH action in this tissue, at room temperature, is independent of noradrenergic signaling. Our data demonstrate that the THAI mouse can also be used to test TH receptor isoform-specific TH action. Thus, THAI mouse constitutes a unique model to study tissue-specific TH action within a physiological/pathophysiological context and test the performance of thyromimetics. In conclusion, THAI mouse provides an in vivo model to assess a high degree of tissue specificity of TH signaling, allowing alteration of tissue function in health and disease, independently of changes in circulating levels of TH.

PMID:
29253128
PMCID:
PMC6283413
DOI:
10.1210/en.2017-00582
[Indexed for MEDLINE]
Free PMC Article

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