Dominant Role of Thyrotropin-releasing Hormone in the Hypothalamic-Pituitary-Thyroid Axis

Amisra A Nikrodhanond,Tania M Ortiga-Carvalho,Nobuyuki Shibusawa,Koshi Hashimoto,Xiao Hui Liao,Samuel Refetoff,Masanobu Yamada,Masatomo Mori,Fredric E Wondisford

doi:10.1074/jbc.m511530200

Amisra A Nikrodhanond, Tania M Ortiga-Carvalho + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m511530200

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Abstract

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.

Highlights

MRNA was absent in thyrotropin-releasing hormone (TRH) KO and double KO mice, whereas thyroid hormone receptors (TRs)␤ KO mice demonstrated an increase in the TRH expression in the paraventricular nucleus (PVN) when compared with WT animals (Fig. 1B)
The physiological set point for thyroid-stimulating hormone (TSH) synthesis and release is determined by a balance between a positive input from hypothalamic TRH and a strong negative influence by thyroid hormone
It has been demonstrated in TR KO animals that TR␤2 is the dominant isoform mediating T3 negative regulation of TSH subunit gene expression in the pituitary and that TR␤2 is the main isoform regulating TRH gene expression in the hypothalamus [16, 20]

Summary

Introduction

TRH KO mice and double KO, in contrast, had only a 3-fold increase in serum TSH levels compared with WT animals. After 35 days of a LoI/PTU diet supplemented with MMI in the water, all mice except the double KO animals presented with undetectable T4 levels (data not shown) and markedly elevated TSH levels (Ͼ10,000 milliunits/liter, Fig. 4A).

Results

Conclusion