Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor α

Paolo E. Macchia, Yoko Takeuchi, Tomoko Kawai, Kevin Cua, Karine Gauthier, Olivier Chassande, Hisao Seo, Yoshitaka Hayashi, Jacques Samarut, Yoshiharu Murata, Roy E. Weiss, Samuel Refetoff

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Abstract

Only three of the four thyroid hormone receptor (TR) isoforms, α1, β1, and β2, bind thyroid hormone (TH) and are considered to be true TRs. TRα2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TRα (TRαo/o) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T4), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3′,5-triiodothyronine, L-T3) given to TH-deprived and to intact TRαo/o mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TRβ(TRβ-/-). In liver, T3 produced significantly greater responses in TRαo/o and smaller responses in TRβ-/- as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TRαo/o, whereas they were similar in WT and TRβ-/- mice, supporting the notion that TRα1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T4 in TRαo/o than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive "silencing" effect of TRα2 in tissues expressing the TRβ isoforms.

Original languageEnglish (US)
Pages (from-to)349-354
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number1
DOIs
StatePublished - Jan 2 2001
Externally publishedYes

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Macchia, P. E., Takeuchi, Y., Kawai, T., Cua, K., Gauthier, K., Chassande, O., Seo, H., Hayashi, Y., Samarut, J., Murata, Y., Weiss, R. E., & Refetoff, S. (2001). Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor α. Proceedings of the National Academy of Sciences of the United States of America, 98(1), 349-354. https://doi.org/10.1073/pnas.011306998