Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary- thyroid axis

Vibha Sharma, William R. Hays, William M. Wood, Umarani Pugazhenthi, Donald L. St Germain, Antonio C. Bianco, Wojciech Krezel, Pierre Chambon, Bryan R. Haugen

Research output: Contribution to journalArticle

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Abstract

Retinoid X receptor (RXR)-selective retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHβ mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHβ mRNA in TαT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TαT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG268 suppressed TSHβ promoter activity by 42% and the -200 to -149 region accounted for a majority of the LG 268-mediated suppression of promoter activity. The RXRγ isotype is expressed in thyrotropes. In vitro transfection and in vivo transgenic studies indicate that any RXR isotype can mediate TSH suppression by rexinoids, but the RXRγ isotype is most efficient at mediating this response. RXRγ-deficient mice lacked pituitary D2mRNAsuppression by LG 268, but D2 activity remained intact. In summary, RXR-selective retinoids (rexinoids) have multiple effects on the hypothalamic-pituitary-thyroid axis. Rexinoids directly suppress TSH secretion, TSHβ mRNA levels and promoter activity, and D2 mRNA levels but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate type 1 iodothyronine deiodinase activity in the liver and pituitary.

Original languageEnglish
Pages (from-to)1438-1451
Number of pages14
JournalEndocrinology
Volume147
Issue number3
DOIs
StatePublished - Mar 1 2006

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Retinoid X Receptors
Thyroid Gland
Messenger RNA
Retinoids
Iodide Peroxidase
Retinoic Acid Receptors
Hypothyroidism
Transfection
LG 268
Rodentia
Cell Line
Liver
Proteins

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Sharma, V., Hays, W. R., Wood, W. M., Pugazhenthi, U., St Germain, D. L., Bianco, A. C., ... Haugen, B. R. (2006). Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary- thyroid axis. Endocrinology, 147(3), 1438-1451. https://doi.org/10.1210/en.2005-0706

Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary- thyroid axis. / Sharma, Vibha; Hays, William R.; Wood, William M.; Pugazhenthi, Umarani; St Germain, Donald L.; Bianco, Antonio C.; Krezel, Wojciech; Chambon, Pierre; Haugen, Bryan R.

In: Endocrinology, Vol. 147, No. 3, 01.03.2006, p. 1438-1451.

Research output: Contribution to journalArticle

Sharma, V, Hays, WR, Wood, WM, Pugazhenthi, U, St Germain, DL, Bianco, AC, Krezel, W, Chambon, P & Haugen, BR 2006, 'Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary- thyroid axis', Endocrinology, vol. 147, no. 3, pp. 1438-1451. https://doi.org/10.1210/en.2005-0706
Sharma V, Hays WR, Wood WM, Pugazhenthi U, St Germain DL, Bianco AC et al. Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary- thyroid axis. Endocrinology. 2006 Mar 1;147(3):1438-1451. https://doi.org/10.1210/en.2005-0706
Sharma, Vibha ; Hays, William R. ; Wood, William M. ; Pugazhenthi, Umarani ; St Germain, Donald L. ; Bianco, Antonio C. ; Krezel, Wojciech ; Chambon, Pierre ; Haugen, Bryan R. / Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary- thyroid axis. In: Endocrinology. 2006 ; Vol. 147, No. 3. pp. 1438-1451.
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