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The Pituitary Function of Androgen Receptor Constitutes a Glucocorticoid Production Circuit

Junko Miyamoto,^1, Takahiro Matsumoto,^1,2, Hiroko Shiina,¹ Kazuki Inoue,¹ Ichiro Takada,¹ Saya Ito,¹ Johbu Itoh,³ Takeo Minematsu,⁴ Takashi Sato,¹ Toshihiko Yanase,⁵ Hajime Nawata,⁵ Yoshiyuki R. Osamura,⁴ and Shigeaki Kato^1,2*

Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan,¹ ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchisi, Saitama 332-0012, Japan,² Teaching and Research Support Center,³ Department of Pathology, Tokai University School of Medicine, Boseidai, Isehara, Kanagawa 259-1193, Japan,⁴ Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan⁵

Received 1 November 2006/ Returned for modification 18 December 2006/ Accepted 16 April 2007

Androgen receptor (AR) mediates diverse androgen actions, particularly reproductive processes in males and females. AR-mediated androgen signaling is considered to also control metabolic processes; however, the molecular basis remains elusive. In the present study, we explored the molecular mechanism of late-onset obesity in male AR null mutant (ARKO) mice. We determined that the obesity was caused by a hypercorticoid state. The negative feedback system regulating glucocorticoid production was impaired in ARKO mice. Male and female ARKO mice exhibited hypertrophic adrenal glands and glucocorticoid overproduction, presumably due to high levels of adrenal corticotropic hormone. The pituitary glands of the ARKO males had increased expression of proopiomelanocortin and decreased expression of the glucocorticoid receptor (GR). There were no overt structural abnormalities and no alteration in the distribution of cell types in the pituitaries of male ARKO mice. Additionally, there was normal production of the other hormones within the glucocorticoid feedback system in both the pituitary and hypothalamus. In a cell line derived from pituitary glands, GR expression was under the positive control of the activated AR. Thus, this study suggests that the activated AR supports the negative feedback regulation of glucocorticoid production via up-regulation of GR expression in the pituitary gland.

Published ahead of print on 30 April 2007.

J.M. and T.M. contributed equally to this work.

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