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

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 5

Illustration depicting the fundamentals of the hypothalamic-pituitary-thyroid axis, including the different sites in which T4-induced D2 ubiquitination plays a role in thyroid hormone homeostasis.

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Illustration depicting the fundamentals of the hypothalamic-pituitary-th...
TRH-expressing neurons release TRH in the portal blood, which is transported to the anterior pituitary. There, TSH is secreted and stimulates the thyroid to produce T4 and T4. In most tissues, exposure to T4 accelerates D2 inactivation by ubiquitination and its targeting to the proteasomal system. UbD2 can also be reactivated and rescued from proteasomal destruction by DUB-mediated deubiquitination. The present findings indicate that peripheral deiodination is very sensitive to T4-induced D2 ubiquitination, and thus a mild elevation in the serum T4/T3 ratio favors D2 inactivation and decreases fractional conversion of T4 to T3 and peripheral T3 production. A similar situation is seen in different regions of the brain where the elevated serum T4/T3 ratio results in a gene expression profile typical of hypothyroidism. In contrast, hypothalamic D2 is less susceptible to T4-induced ubiquitination, and/or deubiquitination is so effective in this tissue that T4-induced D2 inactivation is insignificant. As a result, T4 signaling via D2-mediated T3 production is very effective in the hypothalamus, whereas T3 production via D2 is easily inhibited in the periphery. The situation in the pituitary thyrotrophs is probably intermediary between these two extremes on the basis of previously published data (18). This explains the discrepancy between normalization of TSH secretion and peripheral T3 production observed in L-T4–treated Tx rats.