title: 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.forename: Joao Pedro
authors.initials: JP
authors.lastname: Werneck de Castro
authors.forename: Tatiana L
authors.initials: TL
authors.lastname: Fonseca
authors.forename: Cintia B
authors.initials: CB
authors.lastname: Ueta
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McAninch
authors.forename: Sherine
authors.initials: S
authors.lastname: Abdalla
authors.forename: Gabor
authors.initials: G
authors.lastname: Wittmann
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Lechan
authors.forename: Balazs
authors.initials: B
authors.lastname: Gereben
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
mesh_terms: D000818:Animals; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000201:enzymology*; D007037:Hypothyroidism / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007453:Iodide Peroxidase; D013972:Thyrotropin; D013974:Thyroxine; D044767:Ubiquitin-Protein Ligases; D000097564:Iodothyronine Deiodinase Type II; C503398:Wsb1 protein, mouse