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Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine
Joao Pedro Werneck de Castro, … , Balazs Gereben, Antonio C. Bianco
Joao Pedro Werneck de Castro, … , Balazs Gereben, Antonio C. Bianco
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(2):769-781. https://doi.org/10.1172/JCI77588.
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Research Article Endocrinology

Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine

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Abstract

The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3′-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.

Authors

Joao Pedro Werneck de Castro, Tatiana L. Fonseca, Cintia B. Ueta, Elizabeth A. McAninch, Sherine Abdalla, Gabor Wittmann, Ronald M. Lechan, Balazs Gereben, Antonio C. Bianco

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Figure 1

Parameters of thyroid economy in placebo-control and T4-mono rats plotted as a function of serum T4.

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Parameters of thyroid economy in placebo-control and T4-mono rats plotte...
(A) Serum TSH. (B) Serum T4/T3 ratio. (C) T4-to-T3 fractional conversion. (D) Absolute drop in serum T3 48 hours after daily PTU administration; the percentage drop is also indicated for each group. ***P < 0.001 vs. placebo-control rats. (E) Liver D1 activity. (F) BAT D2 activity. All entries in A–F are the mean ± SD (n = 49–94 per group).

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