Critical role for thyroid hormone receptor beta 2 in the regulation of paraventricular thyrotropin-releasing hormone neurons

Thyroid hormone thyroxine (T-4) and tri-iodothyronine (T-3) production is r egulated by feedback inhibition of thyrotropin (TSH) and thyrotropin-releas ing hormone (TRH) synthesis in the pituitary and hypothalamus when T-3 bind s to thyroid hormone receptors (TRs) interacting with the promoters of the genes for the TSH subunit and TRH, All of the TR isoforms likely participat e 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 p reprothyrotropin-releasing hormone (prepro-TRH) expression in mice lacking the TR-beta2 isoform under basal conditions, after the induction of hypothy roidism with propylthiouracil, and in response to T-3 administration. Prepr o-TRH expression was increased in hypothyroid wild-type mice and markedly s uppressed after T-3 administration. In contrast, basal TRH expression was i ncreased in TR-beta2-null mice to levels seen in hypothyroid wild-type mice and did not change significantly in response to induction of hypothyroidis m or T-3 treatment. However, the suppression of TRH mRNA expression in resp onse 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.