Thyroid hormone thyroxine (T(4)) and tri-iodothyronine (T(3)) production is regulated by feedback inhibition of
thyrotropin (TSH) and
thyrotropin-releasing hormone (TRH) synthesis in the pituitary and hypothalamus when T(3) binds to
thyroid hormone receptors (TRs) interacting with the promoters of the genes for the TSH subunit and TRH. All of the TR
isoforms likely participate in the negative regulation of TSH production in vivo, but the identity of the specific TR
isoforms that negatively regulate TRH production are less clear. To clarify the role of the TR-beta2
isoform in the regulation of TRH gene expression in the hypothalamic paraventricular nucleus, we examined
preprothyrotropin-releasing hormone (
prepro-TRH) expression in mice lacking the TR-beta2
isoform under basal conditions, after the induction of
hypothyroidism with
propylthiouracil, and in response to T(3) administration.
Prepro-TRH expression was increased in hypothyroid wild-type mice and markedly suppressed after T(3) administration. In contrast, basal TRH expression was increased in TR-beta2-null mice to levels seen in hypothyroid wild-type mice and did not change significantly in response to induction of
hypothyroidism or T(3) treatment. However, the suppression of TRH
mRNA expression in response to
leptin reduction during fasting was preserved in TR-beta2-null mice. Thus TR-beta2 is the key TR
isoform responsible for T(3)-mediated negative-feedback regulation by hypophysiotropic TRH neurons.