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J. Biol. Chem., Vol. 281, Issue 8, 5000-5007, February 24, 2006

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

Amisra A. Nikrodhanond¹, Tania M. Ortiga-Carvalho¹, Nobuyuki Shibusawa^¶, Koshi Hashimoto^¶, Xiao Hui Liao, Samuel Refetoff, Masanobu Yamada^¶, Masatomo Mori^¶, and Fredric E. Wondisford²

From the Department of Medicine and the Committee on Molecular Metabolism and Nutrition, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21000-000 Rio de Janeiro, Brazil, and the ^¶Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 3-39-22, Japan

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 isoforms of TH receptors (TR KO), or both (double KO). TR 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.

Received for publication, October 24, 2005 , and in revised form, December 6, 2005.

^* This work was supported by National Institutes of Health Grants DK49126 and DK53036 (to F. E. W.) and Grant DK20595 from the Diabetes Research and Training Center at the University of Chicago. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Metabolism, Depts. of Pediatrics and Medicine, Johns Hopkins Medical Institutes, Baltimore, MD 21287. E-mail: fwondisford{at}jhmi.edu.

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