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This version published online on December 9, 2004
Endocrinology, doi:10.1210/en.2004-1392
A more recent version of this article appeared on March 1, 2005
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Submitted on October 21, 2004
Accepted on December 1, 2004

Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse

Ann Marie Zavacki*, Hao Ying, Marcelo A. Christoffolete, Goele Aerts, Edward So, John W. Harney, Sheue-yann Cheng, P. Reed Larsen, and Antonio C. Bianco

Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston MA 02115 USA; Laboratory of Comparative Endocrinology, K.U. Leuven, 3000 Leuven, Belgium; and Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institute, Bethesda MD 20892 USA

* To whom correspondence should be addressed. E-mail: azavacki{at}rics.bwh.harvard.edu.

Mice with one {alpha}-1 thyroid hormone receptor (TR{alpha}) allele encoding a dominant negative mutant receptor (TR{alpha}1PV/+), have persistently elevated serum T3 levels (1.9-fold normal). They also have markedly increased hepatic type 1 iodothyronine deiodinase (D1) mRNA and enzyme activity (4 to 5-fold), while other hepatic T3-responsive genes such as Spot14 and mitochondrial {alpha}-glycerol phosphate dehydrogenase ({alpha}-GPD) are only 0.7-fold and 1.7-fold that of wild-type littermates (TR{alpha}1+/+). To determine the cause of the disproportionate elevation of D1, TR{alpha}1+/+ and TR{alpha}1PV/+ mice were rendered hypothyroid, then T3-treated. Hypothyroidism decreased hepatic D1, Spot14, and {alpha}-GPD mRNA to similar levels in TR{alpha}1+/+ and TR{alpha}1PV/+ mice, while T3-administration caused ~175-fold elevation of D1 mRNA but only 3 to 6-fold increases in Spot14 and {alpha}-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 iodothyronine deiodinase (D2) activity was 3-times greater in the TR{alpha}1PV/+ mice, and these mice had no T3-dependent induction of type 3 iodothyronine deiodinase (D3). Thus: (i) the marked responsiveness of hepatic D1 to T3 relative to other genes such as Spot14 and {alpha}-GPD explains the relatively large effect of the modest increase in serum T3 in the TR{alpha}1PV/+ mice; (ii) TR{alpha} plays a key role in T3-dependent positive and negative regulation of the deiodinases in the cerebral cortex.
Key words: thyroid • T3 • deiodinase • TR{alpha}1PV/+




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