Nikrodhanond Amisra A, Ortiga-Carvalho Tania M, Shibusawa Nobuyuki, Hashimoto Koshi, Liao Xiao Hui, Refetoff Samuel, Yamada Masanobu, Mori Masatomo, Wondisford Fredric E
Department of Medicine and the Committee on Molecular Metabolism and Nutrition, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
J Biol Chem. 2006 Feb 24;281(8):5000-7. doi: 10.1074/jbc.M511530200. Epub 2005 Dec 8.
Hypothalamic thyrotropin-releasing hormone (TRH) stimulates thyroid-stimulating hormone (TSH) secretion from the anterior pituitary. TSH then initiates thyroid hormone (TH) synthesis and release from the thyroid gland. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback is thought to be the primary regulator. This hypothesis, however, has yet to be proven in vivo. To elucidate the relative importance of TRH and TH in regulating the hypothalamic-pituitary-thyroid axis, we have generated mice that lack either TRH, the beta isoforms of TH receptors (TRbeta KO), or both (double KO). TRbeta knock-out (KO) mice have significantly higher TH and TSH levels compared with wild-type mice, in contrast to double KO mice, which have reduced TH and TSH levels. Unexpectedly, hypothyroid double KO mice also failed to mount a significant rise in serum TSH levels, and pituitary TSH immunostaining was markedly reduced compared with all other hypothyroid mouse genotypes. This impaired TSH response, however, was not due to a reduced number of pituitary thyrotrophs because thyrotroph cell number, as assessed by counting TSH immunopositive cells, was restored after chronic TRH treatment. Thus, TRH is absolutely required for both TSH and TH synthesis but is not necessary for thyrotroph cell development.
下丘脑促甲状腺激素释放激素（TRH）刺激垂体前叶分泌促甲状腺激素（TSH）。TSH随后启动甲状腺激素（TH）的合成并从甲状腺释放。尽管TRH和TH的输入相互拮抗调节下丘脑 - 垂体 - 甲状腺轴，但TH负反馈被认为是主要调节因子。然而，这一假说尚未在体内得到证实。为了阐明TRH和TH在调节下丘脑 - 垂体 - 甲状腺轴中的相对重要性，我们培育了缺乏TRH、TH受体β亚型（TRβ基因敲除小鼠）或两者都缺乏（双基因敲除小鼠）的小鼠。与野生型小鼠相比，TRβ基因敲除（KO）小鼠的TH和TSH水平显著更高，而双基因敲除小鼠的TH和TSH水平则降低。出乎意料的是，甲状腺功能减退的双基因敲除小鼠血清TSH水平也未能显著升高，与所有其他甲状腺功能减退小鼠基因型相比，垂体TSH免疫染色明显减少。然而，这种TSH反应受损并非由于垂体促甲状腺细胞数量减少，因为通过计数TSH免疫阳性细胞评估的促甲状腺细胞数量在慢性TRH治疗后得以恢复。因此，TRH对于TSH和TH的合成绝对必要，但对于促甲状腺细胞的发育并非必需。
