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

J Clin Invest. 2015 Feb;125(2):769-81. doi: 10.1172/JCI77588. Epub 2015 Jan 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Deletion
  • Gene Expression Regulation, Enzymologic / physiology*
  • Humans
  • Hypothalamo-Hypophyseal System / enzymology*
  • Hypothyroidism / drug therapy
  • Hypothyroidism / enzymology
  • Hypothyroidism / genetics
  • Hypothyroidism / pathology
  • Intracellular Signaling Peptides and Proteins
  • Iodide Peroxidase / genetics
  • Iodide Peroxidase / metabolism*
  • Mice
  • Mice, Knockout
  • Rats
  • Thyrotropin / genetics
  • Thyrotropin / metabolism
  • Thyroxine / genetics
  • Thyroxine / metabolism*
  • Thyroxine / pharmacology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / physiology*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Wsb1 protein, mouse
  • Thyrotropin
  • iodothyronine deiodinase type II
  • Iodide Peroxidase
  • Ubiquitin-Protein Ligases
  • Thyroxine