title: The pituitary function of androgen receptor constitutes a glucocorticoid production circuit.
abstract: 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.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Miyamoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shiina
authors.forename: Kazuki
authors.initials: K
authors.lastname: Inoue
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Saya
authors.initials: S
authors.lastname: Ito
authors.forename: Johbu
authors.initials: J
authors.lastname: Itoh
authors.forename: Takeo
authors.initials: T
authors.lastname: Minematsu
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
authors.forename: Yoshiyuki R
authors.initials: YR
authors.lastname: Osamura
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D003345:Corticosterone / Q000097:blood; D013196:Dihydrotestosterone; D025461:Feedback, Physiological; D005260:Female; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000096:biosynthesis*; D006984:Hypertrophy; D007030:Hypothalamo-Hypophyseal System; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000378:metabolism* / Q000473:pathology; D010913:Pituitary-Adrenal System; D011944:Receptors, Androgen / Q000172:deficiency / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D013196:Dihydrotestosterone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone