Thyrotropin Regulation by Thyroid Hormone in Thyroid Hormone Receptor β-Deficient Mice¹

Abstract

Thyroid hormone responsive genes can be both positively and negatively regulated by thyroid hormone. TSH is down-regulated by thyroid hormone and rises during thyroid hormone deprivation. Because both thyroid hormone receptor (TR) alpha and beta genes are expressed in the pituitary gland, it is unclear what the relative roles of TR alpha and TR beta are in TSH regulation. Experiments using over expression of artificial genes have yielded conflicting results. The TR beta knock-out mouse that lacks both TR beta1 and TR beta2 isoforms provides a model to examine the role of these receptors in TSH regulation. TR beta deficient (TR beta-/-) and wild-type (TR beta+/+) mice of the same strain were deprived of thyroid hormone by feeding them a low iodine diet containing propylthiouracil and were then treated with different doses of L-T3 and L-T4. Thyroid hormone deprivation rapidly increased the serum TSH level in both TR beta+/+ and TR beta-/- mice, reaching a similar level in the absence of thyroid hormone. In contrast, the decline of serum TSH by treatment with both L-T3 and L-T4 was severely blunted in TR beta-/- mice, and full suppression was not achieved with the maximal L-T3 dose of 25 microg/day x mouse. These data indicate that TR beta is not required for the up-regulation of TSH in thyroid hormone deficiency. However, although TR alpha alone can mediate thyroid hormone induced TSH suppression, TR beta enhances the sensitivity of TSH down-regulation and may be essential for the complete suppression of TSH.

Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha

“…It is of interest to note that under the current experimental conditions, TH deprivation reduced the expression of 5ЈDI mRNA to undetectable levels in animals of the three genotypes, whereas the reduction in ME mRNA was less pronounced. As is the case with the upregulation of the pituitary TSH gene (20,21,45), downregulation of the liver 5ЈDI gene, during TH deprivation, does not appear to require the presence of TR. TR␣ o/o mice have a significant reduction in heart rate, which increased with the administration of L-T 3 , as previously reported for TR␣1 knockout mice (16).…”

“…Studies were carried out under the conditions of TH deprivation and TH supplementation, according to a previously tested and standardized protocol (15,21,33). This protocol allows the comparison of tissue responses to the same amount of TH in mice that under basal conditions have different concentrations of TH.…”

“…TH deficiency was induced in 10-14 male mice of each type (TR␣ o/o , WT, and TR␤ Ϫ/Ϫ ) with a low-iodine diet containing 0.15% 5-propyl-2-thiouracil (PTU), as described (21). On the 11th day, animals of each type were split into two groups.…”

“…All data generated from this mouse were excluded. Statistics were (14,21), the TR␤ Ϫ/Ϫ animals were resistant to TH and had increased levels of serum T 4 and T 3 as well as TSH concentration. The mean basal heart rate of TR␣ o/o mice was significantly lower than that of WT mice, a finding similar to that reported for mice lacking only the TR␣1 isoform (16).…”

“…To investigate the role of TR␣ in the mediation of TH action, mice were studied during TH deprivation and after supplementation with TH. The dose of 2 g L-T 3 ͞100 g BW (0.5 g͞25 g mouse) has been shown to be effective in bringing the high serum TSH of hypothyroid WT mice to normal, inducing metabolic effects, and producing changes in liver (15,21,33). This investigative approach served two purposes.…”