Both Thyroid Hormone Receptor (TR)β1 and TRβ2 Isoforms Contribute to the Regulation of Hypothalamic Thyrotropin-Releasing Hormone

Abstract

Thyroid hormones (TH) are essential regulators of vertebrate development and metabolism. Central mechanisms governing their production have evolved, with the beta-TH receptor (TRbeta) playing a key regulatory role in the negative feedback effects of circulating TH levels on production of hypothalamic TRH and hypophyseal TSH. Both TRbeta-isoforms (TRbeta1 and TRbeta2) 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 TRbeta vs. TRalpha isoforms in TRH regulation in wild-type mice in vivo by using the TRbeta preferential agonist GC-1. We next determined the effects of tissue-specific rescue of TRbeta1 and TRbeta2 isoforms by somatic gene transfer in hypothalami of TRbeta null (TRbeta(-/-)) mice. TH-dependent TRH transcriptional repression was impaired in TRbeta(-/-) mice, but was restored by cotransfection of either TRbeta1 or TRbeta2 into the hypothalamus. TRbeta1, but not TRbeta2, 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 TRbeta(-/-) or TRalpha null (TRalpha(o/o)) mice under different thyroid states. In contrast to published data on TRbeta2(-/-) mice, we found that both ligand-independent TRH activation and ligand-dependent TRH repression were severely impaired in TRbeta(-/-) mice. This study thus provides functional in vivo data showing that both TRbeta1 and TRbeta2 isoforms have specific roles in regulating TRH transcription.

Thyrotropin-producing pituitary adenoma associated with Graves' disease

“…Generation of an abnormal TRb alternative splicing variant mediated by post-transcriptional mechanisms has recently been considered as a potential cause of the defective negative feedback of thyroid hormone on TSH production, and may also contribute to uncontrolled tumor growth in TSHoma (19,21). Quite recently, Dupre et al (22) reported that TRb isoforms (TRb1 and TRb2) are expressed in the hypothalamus and involved in the regulation of hypothalamic TRH. Both inappropriate TSH secretion and uncontrolled tumor growth in TSHoma may be due to defective negative feedback of thyroid hormone on TRH production by abnormal TRb in the hypothalamus.…”

Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression

“…TRH-f.luc and TRα1, TRβ1, and TRβ2 plasmids were as described (27). MC4R-f.luc plasmid, provided by H. Krude (Charity Medical University, Berlin, Germany), contains −653 to +448 bp of the MC4R promoter cloned upstream of the Firefly luciferase-coding sequence of the pGL3 basic Luciferase reporter vector (Promega, Charbonniéres les Bains, France).…”

Negative Regulation of the Thyrotropin β Gene by Thyroid Hormone

“…However, there are few experimental studies that show the molecular mechanism by which these putative nTREs reverse the function of T3/TR from transcriptional activator to repressor. In TR -and/or TR 1-deficient mice, the expression of GSU (Forrest et al, 1996;Gothe et al, 1999) in the pituitary, prepro-TRH in the hypothalamus (Abel et al, 2001;Dupre et al, 2004) and MHC in the heart (Mansen et al, 2001) are maintained, suggesting that, as in the case of the TSH gene, the basal activities of these genes are also maintained by a transcriptional activator other than unliganded TR. Thus, existence of nTREs in these genes should also be reconsidered.…”