CoChat
Sign Up
Cited by 18Thyroid Disorders and TreatmentsGrowth Hormone and Insulin-like Growth FactorsThyroid Cancer Diagnosis and Treatment

Sustained Pituitary T3 Production Explains the T4-mediated TSH Feedback Mechanism

Open access
Batistuzzo, Alice, Salas-Lucia, Federico, Gereben, Balázs, Ribeiro, Miriam O, Bianco, Antonio C·2023·Endocrinology
DOI 10.1210/endocr/bqad155PMC PMC10637099
Open this paper in CoChat — free accountOpen PDF

Abstract

The regulation of thyroid activity and thyroid hormone (TH) secretion is based on feedback mechanisms that involve the anterior pituitary TSH and medial basal hypothalamus TSH-releasing hormone. Plasma T3 levels can be “sensed” directly by the anterior pituitary and medial basal hypothalamus; plasma T4 levels require local conversion of T4 to T3, which is mediated by the type 2 deiodinase (D2). To study D2-mediated T4 to T3 conversion and T3 production in the anterior pituitary gland, we used mouse pituitary explants incubated with 125I-T4 for 48 hours to measure T3 production at different concentrations of free T4. The results were compared with cultures of D1- or D2-expressing cells, as well as freshly isolated mouse tissue. These studies revealed a unique regulation of the D2 pathway in the anterior pituitary gland, distinct from that observed in nonpituitary tissues. In the anterior pituitary, increasing T4 levels reduced D2 activity slightly but caused a direct increase in T3 production. However, the same changes in T4 levels decreased T3 production in human HSkM cells and murine C2C12 cells (both skeletal muscle) and mouse bone marrow tissue, which reached zero at 50 pM free T4. In contrast, the increase in T4 levels caused the pig kidney LLC-PK1 cells and kidney fragments to proportionally increase T3 production. These findings have important implications for both physiology and clinical practice because they clarify the mechanism by which fluctuations in plasma T4 levels are transduced in the anterior pituitary gland to mediate the TSH feedback mechanism.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1210/endocr/bqad155

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In human skeletal muscle, D2-mediated T3 production drops by approximately 50% with the increase in FT4 from 10 to 20 pM, reaching nearly zero at 30 pM FT4.

    “In human skeletal muscle, for example, D2-mediated T3 production drops by approximately 50% with the increase in FT4 from 10 to 20 pM, reaching nearly zero at 30 pM FT4 (46).”

    From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [46]

    In “T3 Production in Skeletal Muscle and Kidney Cell Lines at Different Free T4 Concentrations,” the paper says T3 production in human skeletal muscle cells remained stable as free T4 rose from 10 to 20 pM, rather than dropping by about 50%. It reports production reaching zero at 50 pM, not 30 pM. The supplied passages do not give page numbers. (LLM, conf=0.91)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 48

  1. Bianco AC, Dumitrescu A, Gereben B, et al. Paradigms of dynamic control of thyroid hormone signaling. Endocr Rev. 2019;40(4): 1000-1047.
  2. St. Germain DL. Hormonal control of a low Km (type II) iodothyr- onine 5′-deiodinase in cultured NB41A3 mouse neuroblastoma cells. Endocrinology. 1986;119(2):840-846.
  3. Leonard JL, Siegrist-Kaiser CA, Zuckerman CJ. Regulation of type II iodothyronine 5′-deiodinase by thyroid hormone. Inhibition of actin polymerization blocks enzyme inactivation in cAMP-stimu- lated glial cells. J Biol Chem. 1990;265(2):940-946.
  4. Silva JE, Leonard JL. Regulation of rat cerebrocortical and adeno- hypophyseal type II 5′-deiodinase by thyroxine, triiodothyronine, and reverse triiodothyronine. Endocrinology. 1985;116(4): 1627-1635.
  5. Fukuda H, Yasuda N, Greer MA, Kutas M, Greer SE. Changes in plasma thyroxine, triiodothyronine, and TSH during adaptation to iodine deficiency in the rat. Endocrinology. 1975;97(2):307-314.
  6. Silva E. Disposal rates of thyroxine and triiodothyronine in iodine- deficient rats. Endocrinology. 1972;91(6):1430-1435.
  7. Abrams GM, Larsen PR. Triiodothyronine and thyroxine in the se- rum and thyroid glands of iodine-deficient rats. J Clin Invest. 1973;52(10):2522-2531.
  8. Chopra IJ, Hershman JM, Hornabrook RW. Serum thyroid hor- mone and thyrotropin levels in subjects from endemic goiter regions of New Guinea. J Clin Endocrinol Metab. 1975;40(2):326-333.
  9. Silva JE, Kaplan MM, Cheron RG, Dick TE, Larsen PR. Thyroxine to 3,5,3′-triiodothyronine conversion by rat anterior pituitary and liver. Metabolism. 1978;27(11):1601-1607.
  10. Abend SL, Fang SL, Alex S, Braverman LE, Leonard JL. Rapid al- teration in circulating free thyroxine modulates pituitary type II 5′deiodinase and basal thyrotropin secretion in the rat. J Clin Invest. 1991;88(3):898-903.
  11. Maeda M, Ingbar SH. Effect of alterations in thyroid status on the metabolism of thyroxine and triiodothyronine by rat pituitary gland in vitro. J Clin Invest. 1982;69(4):799-808.
  12. Curty FH, Lisboa PC, Ortiga-Carvalho TM, Pazos-Moura CC. The somatostatin analogue octreotide modulates iodothyronine deiodi- nase activity and pituitary neuromedin B. Thyroid. 2000;10(8): 647-652.
  13. Shupnik MA, Chin WW, Habener JF, Ridgway EC. Transcriptional regulation of the thyrotropin subunit genes by thyroid hormone. J Biol Chem. 1985;260(5):2900-2903.
  14. Larsen PR. Thyroid-pituitary interaction: feedback regulation of thyrotropin secretion by thyroid hormones. New Engl J Med. 1982;306(1):23-32.
  15. Baqui MM, Gereben B, Harney JW, Larsen PR, Bianco AC. Distinct subcellular localization of transiently expressed types 1 and 2 iodo- thyronine deiodinases as determined by immunofluorescence con- focal microscopy. Research support, U.S. Gov't, P.H.S. Endocrinology. 2000;141(11):4309-4312.
  16. Curcio C, Baqui MM, Salvatore D, et al. The human type 2 iodo- thyronine deiodinase is a selenoprotein highly expressed in a meso- thelioma cell line. Research support, U.S. Gov't, P.H.S. J Biol Chem. 2001;276(32):30183-30187.
  17. Ruf-Zamojski F, Zhang Z, Zamojski M, et al. Single nucleus multi-omics regulatory landscape of the murine pituitary. Nat Commun. 2021;12(1):2677.
  18. Tanaka K, Shimatsu A, Imura H. Iodothyronine 5-deiodinase in rat posterior pituitary. Biochem Biophys Res Commun. 1992;188(1): 272-277.
  19. Medina MC, Molina J, Gadea Y, et al. The thyroid hormone- inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion. Endocrinology. 2011;152(10):3717-3727.
  20. Gouveia CH, Christoffolete MA, Zaitune CR, et al. Type 2 iodo- thyronine selenodeiodinase is expressed throughout the mouse skel- eton and in the MC3T3-E1 mouse osteoblastic cell line during differentiation. Endocrinology. 2005;146(1):195-200.
  21. Yaffe D, Saxel O. Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle. Nature. 1977; 270(5639):725-727.
  22. Hull RN, Cherry WR, Weaver GW. The origin and characteristics of a pig kidney cell strain, LLC-PK. In Vitro. 1976;12(10):670-677.
  23. An X, Ogawa-Wong A, Carmody C, et al. A type 2 deiodinase- dependent increase in Vegfa mediates myoblast-endothelial cell crosstalk during skeletal muscle regeneration. Thyroid. 2021;31(1):115-127.
  24. Leonard JL, Ekenbarger DM, Frank SJ, Farwell AP, Koehrle J. Localization of type I iodothyronine 5′-deiodinase to the basolater- al plasma membrane in renal cortical epithelial cells. J Biol Chem. 1991;266(17):11262-11269.
  25. Grozovsky R, Ribich S, Rosene ML, et al. Type 2 deiodinase expres- sion is induced by peroxisomal proliferator-activated receptor- gamma agonists in skeletal myocytes. Endocrinology. 2009;150(4): 1976-1983.
  26. Parra-Montes de Oca MA, Sotelo-Rivera I, Gutierrez-Mata A, Charli JL, Joseph-Bravo P. Sex dimorphic responses of the hypothalamus-pituitary-thyroid axis to energy demands and stress. Front Endocrinol (Lausanne). 2021;12:746924.
  27. Marassi MP, Fortunato RS, da Silva AC, et al. Sexual dimorphism in thyroid function and type 1 iodothyronine deiodinase activity in pre-pubertal and adult rats. J Endocrinol. 2007;192(1):121-130.
  28. Schomburg L, Bauer K. Regulation of the adenohypophyseal thyrotropin-releasing hormone-degrading ectoenzyme by estradiol. Endocrinology. 1997;138(9):3587-3593.
  29. Larsen PR, Silva JE, Kaplan MM. Relationships between circulat- ing and intracellular thyroid hormones: physiological and clinical implications. Endocr Rev. 1981;2(1):87-102.
  30. Dentice M, Marsili A, Ambrosio R, et al. The FoxO3/type 2 deiodi- nase pathway is required for normal mouse myogenesis and muscle regeneration. J Clin Invest. 2010;120(11):4021-4030.
  31. Marsili A, Tang D, Harney JW, et al. Type II iodothyronine deiodi- nase provides intracellular 3,5,3′-triiodothyronine to normal and regenerating mouse skeletal muscle. Am J Physiol Endocrinol Metab. 2011;301(5):E818-E824.
  32. Hosoi Y, Murakami M, Mizuma H, Ogiwara T, Imamura M, Mori M. Expression and regulation of type II iodothyronine deiodinase in cultured human skeletal muscle cells. J Clin Endocrinol Metab. 1999;84(9):3293-3300.
  33. Ettleson MD, Prieto WH, Russo PST, et al. Serum thyrotropin and triiodothyronine levels in levothyroxine-treated patients. J Clin Endocrinol Metab. 2022;108(6):e258-e266.
  34. St Germain DL, Adler RA, Galton VA. Thyroxine 5′-deiodinase ac- tivity in anterior pituitary glands transplanted under the renal cap- sule in the rat. Endocrinology. 1985;117(1):55-63.
  35. Sagar GD, Gereben B, Callebaut I, et al. Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. Mol Cell Biol. 2007;27(13):4774-4783.
  36. Zavacki AM, Arrojo EDR, Freitas BC, et al. The E3 ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine deiodinase. Mol Cell Biol. 2009;29(19):5339-5347.
  37. Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activa- tion. Nature. 2006;439(7075):484-489.
  38. Arrojo EDR, Egri P, Jo S, Gereben B, Bianco AC. The type II deio- dinase is retrotranslocated to the cytoplasm and proteasomes via p97/Atx3 complex. Mol Endocrinol. 2013;27(12):2105-2115.
  39. Curcio-Morelli C, Zavacki AM, Christofollete M, et al. Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regu- lates thyroid hormone activation. J Clin Invest. 2003;112(2): 189-196.
  40. Steinsapir J, Bianco AC, Buettner C, Harney J, Larsen PR. Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme's Active center. Endocrinology. 2000;141(3):1127-1135.
  41. Nicoloff JT, Lum SM, Spencer CA, Morris R. Peripheral autoregu- lation of thyroxine to triiodothyronine conversion in man. Horm Metab Res Suppl. 1984;14:74-79.
  42. Silva JE, Gordon MB, Crantz FR, Leonard JL, Larsen PR. Qualitative and quantitative differences in the pathways of extra- thyroidal triiodothyronine generation between euthyroid and hypothyroid rats. J Clin invest. 1984;73(4):898-907.
  43. Dentice M, Bandyopadhyay A, Gereben B, et al. The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thy- roid hormone activation and PTHrP secretion in the developing growth plate. Research support, N.I.H., extramural research sup- port, U.S. Gov't, P.H.S. Nat Cell Biol. 2005;7(7):698-705.
  44. Zhang X, Jiang Y, Han W, et al. Effect of prolonged iodine over- dose on type 2 iodothyronine deiodinase ubiquitination-related en- zymes in the rat pituitary. Biol Trace Elem Res. 2016;174(2): 377-386.
  45. Baur A, Kohrle J. Type 1 deiodinase is stimulated by iodothyronines and involved in thyroid hormone metabolism in human somato- mammotroph GX cells. Eur J Endocrinol. 1999;140(4):367-370.
  46. Baur A, Bauer K, Jarry H, Kohrle J. 3,5-diiodo-L-thyronine Stimulates type 1 5′deiodinase activity in rat anterior pituitaries in vivo and in reaggregate cultures and GH3 cells in vitro. Endocrinology. 1997;138(8):3242-3248.
  47. Baur A, Buchfelder M, Kohrle J. Expression of 5′-deiodinase en- zymes in normal pituitaries and in various human pituitary aden- omas. Eur J Endocrinol. 2002;147(2):263-268.
  48. Tannahill LA, Visser TJ, McCabe CJ, et al. Dysregulation of iodo- thyronine deiodinase enzyme expression and function in human pi- tuitary tumours. Clin Endocrinol (Oxf). 2002;56(6):735-743.

Cited by

Sorted by citations

Authors
Batistuzzo, A., Salas-Lucia, F., Gereben, B., Ribeiro, M. O., & Bianco, A. C.
Affiliations
  • University of Chicago (US)
  • HUN-REN Institute of Experimental Medicine (HU)
  • Universidade Presbiteriana Mackenzie (BR)
Corresponding author
Bianco, Antonio C
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2023-10-21
Volume
164
Issue
12
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/endocr/bqad155
PMC
PMC10637099
OpenAlex
W4387854798
Cited by
18
References
14
Citations by year
2026: 6 · 2025: 7 · 2024: 4 · 2023: 1
FWCI
3.69
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • Endocrinology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (cc-by)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK15070, DK65066, DK77148, DK58538)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
type 2 deiodinase, T4 to T3 conversion, anterior pituitary, thyroid hormone regulation, thyroid-stimulating hormone, skeletal muscle, kidney, bone marrow
MeSH terms
Animals, Feedback, Humans, Iodine Radioisotopes, Pituitary Gland, Swine, Thyrotropin, Thyroxine, Triiodothyronine, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review