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

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.

Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

“…It appears that adequate intracellular T 3 concentration in the BAT is necessary for cold-induced thermogenesis in mice [29,38]. This is also evident in the clinical setting, as severely hypothyroid patients can present with hypothermia and are at increased risk of myxedema coma.…”

“…Additionally, it appears that autophagy (particularly, mitophagy) is critical for the TH-induced thermogenesis in the BAT as the BAT-specific autophagy-related protein 5 (Atg5) knockdown in mice abrogates the activated thermogenesis [22]. Interestingly, Mohácsik et al used a reporter mouse that detects TH transcriptional activity, and find that TH activation of the BAT is of 16 dependent upon noradrenergic stimulation during cold exposure, but is independent of noradrenergic signaling at room temperature [38]. Therefore, both central and peripheral effects of TH are responsible for coordinated activation of thermogenesis in the BAT.…”

Regulation of T3 Availability in the Developing Brain: The Mouse Genetics Contribution

“…Two simpler, but less specific, transgenic devices have also been produced: TRE2x mice carry the lacZ gene, the expression of which is driven by a minimal promoter and two binding sites for endogenous TR ( 52 ). THAI mice design followed a similar strategy, but the luciferase gene was preferred to lacZ to facilitate quantification and live imaging ( 53 ). The lacZ reporter expression patterns in FINDT3 and TRE2x mice do not always match.…”

“…Although this is expected, as they rely on very different systems, the presence of experimental biases cannot be completely ruled out, as both systems could be influenced by other factors than T3 local concentration. For example, TRE2x is also regulated by other nuclear receptors recognizing the same response element, notably LXR ( 53 ). Meanwhile, the minimal promoter used in FINDT3 mice favors the expression in neurons but is inefficient in glia ( 50 ).…”

We All Know We Need Them, We Hope They Are Coming, But When?

“…The usefulness of assessing TH on a tissue-specific manner has been demonstrated experimentally in a number of animal models. For example, important tissue-specific differences in TH signaling were identified in a mouse model that carries a luciferase-based reporter gene that is responsive to TH (14). In the clinical setting, however, we need a noninvasive approach to study TH signaling.…”