Role of D3 in the development of the hypothalamus-pituitary-thyroid axis

TOPIC: Thyroid hormone metabolism & action

Title: Type 2 deiodinase deficiency results in functional abnormalities at multiple levels of the thyroid axis.

Authors: Hernandez A, Martinez ME, Liao XH, Van Sande J, Refetoff S, Galton VA, & St Germain DL.

Reference: Endocrinology 148: 5680-5687, 2007

Summary

Background

The type 3 deiodinase (D3) is a selenoenzyme that inactivates thyroid hormones and is highly expressed during development and in the adult central nervous system. The authors have recently observed that mice lacking D3 activity (D3KO mice) develop perinatal thyrotoxicosis, followed in adulthood by a pattern of hormonal levels that is suggestive of central hypothyroidism.

Results

The authors describe the results of additional studies designed to investigate the regulation of the thyroid axis in this unique animal model. The results demonstrate that the thyroid and pituitary glands of D3KO mice do not respond appropriately to TSH and TRH stimulation, respectively. Furthermore, after induction of severe hypothyroidism by antithyroid drug treatment, the rise in serum TSH in D3KO mice is only 15% of that observed in wild-type mice. In addition, D3KO animals rendered severely hypothyroid fail to show the expected increase in prepro-TRH mRNA in the paraventricular nucleus of the hypothalamus. Finally, treatment with T 3 results in a serum T 3 level in D3KO mice that is much higher than that in wild-type mice. This is accompanied by significant weight loss and lethality in mutant animals.

Conclusions

Absence of D3 activity resulted in impaired clearance of T 3 and significant defects in the mechanisms regulating the thyroid axis at all levels, the hypothalamus, the pituitary, and the thyroid.

Commentary

Compared with type 1 (D1) and type 2 (D2) deiodinase knockout mice, the phenotype of D3 knockout mice (all generated by the group of Schneider, Hernandez, Galton & St Germain in Lebanon, NH, USA) is much more severe as it is associated with significant mortality and morbidity. Previous studies with these mice have established that D3 gene expression is subjected to imprinting, with predominant expression from the paternal allele and little contribution from the maternal allele.

Further studies published in the J Clin Invest (116: 476-485, 2007) showed that in the first week of life, serum T 3 rises faster in the D3-/- mice than in D3+/+ mice, but decrease subsequently to markedly lower levels in KO than in WT animals. Serum T 4 free online pokies game remains very low in the KO animals until weaning and increase thereafter to remain lower than in WT mice. Despite the lower serum T 4 and T 3 levels in KO mice, serum TSH is not different or only moderately increased compared with WT animals, suggesting a state of central hypothyroidism. D3 is normally expressed in the hypothalamus where it plays a role in the regulation of local T3 levels and, thus, in the negative feedback control of TRH production and secretion. Continuous exposure of TRH neurons to elevated T 3 levels during brain development apparently results in the maintenance of an abnormal setting point of the hypothalamus-pituitary thyroid (HPT) axis.

The authors have further explored the HPT axis in D3 KO vs WT mice, and the results of this study indicate abnormalities at all levels of the HPT axis. Methimazole-induced hypothyroidism results in a much lower up-regulation of hypothalamic TRH expression in D3 KO than in WT mice. It is not excluded that this is explained by still higher hypothalamic T 3 levels in the KO vs WT mice. TRH administration induces markedly smaller increases in serum TSH in D3 KO mice than in WT animals, despite the lower thyroid hormone levels in the former than in the latter. Most remarkable, however, are the findings that TSH treatment induces a marked increase in serum T 4 in WT animals but no increase at all in KO mice. Therefore, inactivation of D3 is associated with an impaired function of the thyroid gland, indicating that these animals have both central and primary hypothyroidism.

These studies appear to be related to the findings of central hypothyroidism in the offspring of women with active Graves' disease during pregnancy (see. Kempers et al. , JCEM 88: 5851-5857, 2003). Central hypothyroidism in this clinical context is correlated with exposure of the fetus to high thyroid hormone levels, rather than the presence of maternal autoantibodies. Also in these infants, the state of central hypothyroidism is associated with a loss of thyroid integrity and function (see Kempers et al. , JCEM 92: 2984-2991, 2007).

Further studies in D3 KO mice may help to unravel how a diminished activity of the HPT axis may lead to a functional impairment of the thyroid.

Summary and commentary prepared by Theo Visser (Related to Chapter 3 – Sections 3c & 3d – of TDM)