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.