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

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 Thyroid Hormone Action Indicator (THAI)-Mouse model to study tissue-specific TH action. The model utilizes a Firefly Luciferase reporter readout in the context of an intact transcriptional apparatus and all elements of TH metabolism and transport and signalling. THAI mouse allows the assessment of the changes of TH signalling in tissue samples or in live animals using bioluminescence both in hypo- and hyperthyroidism. Beyond pharmacologically manipulated TH levels, THAI mouse is sufficiently sensitive to detect deiodinase-mediated changes of TH action in the interscapular BAT in cold environment during preserving thermal homeostasis. The model allowed to reveal 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 signalling. Our data demonstrate that the THAI mouse can be also utilized to test TR 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 signalling allowing to alter tissue function in health and disease independently of changes in circulating levels of TH.