Both thyroid hormone receptor (TR)β1 and TRβ2 isoforms contribute to the regulation of hypothalamic Thyrotropin-Releasing Hormone

Thyroid hormones (TH) are essential regulators of vertebrate development and metabolism. Central mechanisms governing their production have evolved, with the β-TH receptor (TRβ) playing a key regulatory role in the negative feedback effects of circulating TH levels on production of hypothalamic TRH and hypophyseal TSH. Both TRβ-isoforms (TRβ1 and TRβ2) are expressed in the hypothalamus and pituitary. However, their respective roles in TH-dependent transcriptional regulation of TRH are undefined. We confirmed the preferential role of TRβ vs. TRα isoforms in TRH regulation in wild-type mice in vivo by using the TRβ preferential agonist GC-1. We next determined the effects of tissue-specific rescue of TRβ1 and TRβ2 isoforms by somatic gene transfer in hypothalami of TRβ null (TRβ^-/-) mice. TH-dependent TRH transcriptional repression was impaired in TRβ^-/- mice, but was restored by cotransfection of either TRβ1 or TRβ2 into the hypothalamus. TRβ1, but not TRβ2, displayed a role in ligand-independent activation. In situ hybridization was used to examine endogenous TRH expression in the paraventricular nucleus of the hypothalamus of TRβ^-/- or TRα null (TRα^o/o) mice under different thyroid states. In contrast to published data on TRβ2^-/- mice, we found that both ligand-independent TRH activation and ligand-dependent TRH repression were severely impaired in TRβ^-/- mice. This study thus provides functional in vivo data showing that both TRβ1 and TRβ2 isoforms have specific roles in regulating TRH transcription.