The hypothalamic paraventricular nucleus is the center of the hypothalamo-pituitary-thyroid axis for regulating thyroid hormone levels.

Background Thyrotropin-releasing hormone (TRH) was the first hypothalamic hormone isolated that stimulates pituitary thyroid-stimulating hormone (TSH) secretion. TRH was also later found to be a stimulator of pituitary prolactin and distributed throughout the brain, gastrointestinal tract, and pancreatic β cells. We previously reported the development of TRH null mice (conventional TRHKO), which exhibit characteristic tertiary hypothyroidism and impaired glucose tolerance due to insufficient insulin secretion. Although in the last five decades many investigators, us included, have attempted to determine the hypothalamic nucleus responsible for the hypothalamo-pituitary-thyroid (HPT) axis, it remained obscure because of the broad expression of TRH. Methods To determine the part of the hypothalamic region functionally responsible for the hypothalamo-pituitary-thyroid (HPT) axis, we established paraventricular nucleus (PVN)-specific TRH knock-out (PVN-TRHKO) mice by mating Trh floxed mice and Sim1-Cre transgenic mice. We originally confirmed that most Sim1 was expressed in the paraventricular nucleus using Sim1-Cre/tdTomato mice. Results These PVN-TRHKO mice exhibited tertiary hypothyroidism similar to conventional TRHKO mice, however, they did not show the impaired glucose tolerance observed in the latter, suggesting that TRH from non-PVN sources is essential for glucose regulation. In addition, a severe reduction in prolactin expression was observed in the pituitary of PVN-TRHKO mice compared with that in TRHKO mice. Conclusions These findings are conclusive evidence that the PVN is the center of the HPT axis for regulation of serum levels of thyroid hormones, and that the serum TSH levels are not decreased in tertiary hypothyroidism. We also noted that TRH from the PVN regulated prolactin, whereas TRH from non-PVN sources regulated glucose metabolism.