ArticleThe Journal of clinical investigation2015
Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
105 citing papers in PubMed, 2 syntheses or guidelines pooled it, 180 citations in OpenAlex.
- Treatment Preferences in Patients With Hypothyroidism.The Journal of clinical endocrinology and metabolism · 2025Pooled it
- Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document.Thyroid : official journal of the American Thyroid Association · 2021Guideline
- A feasibility double-blind trial of levothyroxine vs. levothyroxine-liothyronine in postsurgical hypothyroidism.Frontiers in endocrinology · 2025Trial
- Pharmacodynamic and pharmacokinetic properties of the combined preparation of levothyroxine plus sustained- release liothyronine; a randomized controlled clinical trial.BMC endocrine disorders · 2023Trial
- Extended Absorption of Liothyronine from Poly-Zinc-Liothyronine: Results from a Phase 1, Double-Blind, Randomized, and Controlled Study in Humans.Thyroid : official journal of the American Thyroid Association · 2022Trial
- Quality of life in hypothyroid subjects treated with levothyroxine: a cross-sectional study.Thyroid research · 2026Article
- Thyroid hormone measurement items in patients with Hashimoto's thyroiditis on levothyroxine monotherapy: management based on thyroid tissue volume.Thyroid research · 2026Article
- Signal Amplification in the HPT Axis-Evidence for Its Existence, Location, Significance, and Molecular Mechanisms.Acta physiologica (Oxford, England) · 2026Review
- Association between impaired peripheral thyroid hormone sensitivity and coronary heart disease in type 2 diabetes: the potential mediating role of albumin.Frontiers in endocrinology · 2026Article
- The relationship between levothyroxine dosage and free thyroxine levels in hypothyroid patients: a large retrospective study.European thyroid journal · 2025Article
- A Genetically-Engineered Thyroid Gland Built for Selective Triiodothyronine Secretion.International journal of molecular sciences · 2025Article
- FT3 and FT3/FT4 ratio are decreased and not compensated by levothyroxine treatment in TKI-treated thyroid cancer patients.Endocrine-related cancer · 2025Article
- Psychological factors and obesity, not thyroid biomarkers, predict thyroid-dependent quality of life in treated hypothyroidism: a cross-sectional study.BMC endocrine disorders · 2025Article
- FVB But Not B6 Mice Carrying the Thr92Ala-Dio2 Polymorphism Have Impaired Thyroid Hormonogenesis and Goiter.Endocrinology · 2025Article
- Variable transduction of thyroid hormone signaling in structures of the mouse brain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Current status of the thyroid hormone measurement items in patients receiving levothyroxine monotherapy by the management based on the thyroid tissue volume.Endocrine journal · 2025Article
- Persistent symptoms in euthyroid Hashimoto's thyroiditis: current hypotheses and emerging management strategies.Frontiers in endocrinology · 2025Review
- Clinical thyroidology: beyond the 1970s' TSH-T4 Paradigm.Frontiers in endocrinology · 2025Review
- Levothyroxine therapy in thyroidectomized patients: ongoing challenges and controversies.Frontiers in endocrinology · 2025Review
- Metabolic Consequences of Thyroidectomy and Patient-Centered Management.Journal of clinical medicine · 2024Review
45 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.