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. 2007 Jul;27(13):4807-14.
doi: 10.1128/MCB.02039-06. Epub 2007 Apr 30.

The pituitary function of androgen receptor constitutes a glucocorticoid production circuit

Junko Miyamoto  1 , Takahiro Matsumoto, Hiroko Shiina, Kazuki Inoue, Ichiro Takada, Saya Ito, Johbu Itoh, Takeo Minematsu, Takashi Sato, Toshihiko Yanase, Hajime Nawata, Yoshiyuki R Osamura, Shigeaki Kato
Affiliations

The pituitary function of androgen receptor constitutes a glucocorticoid production circuit

Junko Miyamoto et al. Mol Cell Biol. 2007 Jul.

Erratum in

  • Mol Cell Biol. 2014 Mar;34(5):914

Expression of concern in

  • Publisher's expression of concern.
    [No authors listed] [No authors listed] Mol Cell Biol. 2013 Jun;33(12):2508. doi: 10.1128/MCB.00356-13. Mol Cell Biol. 2013. PMID: 23698641 Free PMC article.

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.

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Figures

FIG. 1.
FIG. 1.
Hypertrophic adrenal glands with high serum levels of ACTH and corticosterone in ARKO mice. (A) Growth curves of ARKO and WT littermate mice. The floxed AR mice (female, ARL+/L+; male, ARL+/Y) were crossed with Cre-CMV transgenic mice to generate ARKO male (ARL−/Y) and female (ARL−/L−) mice (16, 30). (B) Serum corticosterone levels of ARKO and WT mice at 2, 8, 13, and 20 weeks (W) of age. (C) Plasma ACTH levels of ARKO and WT mice measured in the morning (8:00) and evening (18:00). (D) Serum corticosterone levels of ARKO and WT mice in the morning (8:00) and evening (18:00). (E) Adrenal gland weights of male and female ARKO and WT mice at 2, 8, 13, and 20 weeks of age. (F) Histology of ARKO and WT adrenal glands. All sections were stained with hematoxylin and eosin. F, zona fasciculata; G, zona glomerulosa; X, X-zone.
FIG. 2.
FIG. 2.
Increased proliferation and decreased apoptosis in ARKO adrenal glands. (A) Decreased apoptosis in the ARKO adrenal glands. Histogram showing the number of TUNEL-positive cells in the zona fasciculata (Z. fasciculata). (B) Increased proliferation in the ARKO adrenal cortex. Histogram showing the number of BrdU-positive cells.
FIG. 3.
FIG. 3.
Impairment of the HPA negative feedback system of glucocorticoid production in ARKO mice. (A) Serum corticosterone levels of ARKO and WT mice in the dexamethasone suppression test. Trunk blood was collected from ARKO and WT mice 6 hours after injection with increasing doses of dexamethasone. (B) Plasma ACTH levels of ARKO and WT mice in the dexamethasone suppression test.
FIG. 4.
FIG. 4.
Histological appearance of the hypothalamus and pituitary gland in ARKO mice. (A) No clear alteration in morphology of the hypothalami or pituitary glands of ARKO mice. Sections of pituitary glands and hypothalami were stained with hematoxylin and eosin. A, anterior lobe; M, intermediate lobe; P, posterior lobe. (B) No overt abnormality in the distribution of cells expressing pituitary hormones in ARKO mice by immunohistochemical staining. LHβ, luteinizing hormone β; FSHβ, follicle-stimulating hormone β; TSHβ, thyroid-stimulating hormone β; CGA, glycoprotein hormone; PRL, prolactin; GH, growth hormone. (C) Pituitary ACTH (black/gray) colocalized with AR (brown) or GR (brown) (left) and its higher magnification (right) in WT mice as detected by immunostaining with specific antibodies. (D) No clear alterations in the GR and CRH (in the paraventricular nucleus) and α-MSH (in the arcuate nucleus) immunoreactive neurons in the hypothalami of ARKO mice.
FIG. 5.
FIG. 5.
Altered expression levels of gene transcripts involved in the HPA axis. (A) Increased POMC and decreased GR expression levels of transcripts in ARKO pituitary by semiquantitative RT-PCR. LHβ, luteinizing hormone β; FSHβ, follicle-stimulating hormone β; TSHβ, thyroid-stimulating hormone β. (B) No significant alterations of POMC and GR mRNA levels in the pituitary glands of female ARKO (ARL−/L−) mice. (C and D) Northern blot analyses showing clear up-regulation of POMC mRNA levels and down-regulation of GR mRNA levels in the ARKO pituitary. (E) Tissue-specific reduction of GR transcripts in ARKO mice. GR expression levels are down-regulated only in the spleen and pituitary in male ARKO mice.
FIG. 6.
FIG. 6.
Cell-type-specific regulation of the GR by activated AR. (A) Regulation of GR and POMC gene expression by treatment with either DHT or an AR antagonist (Flutamide) in the cultured cells as analyzed by Northern blot analysis. (B) Expression of the GR and pro-ACTH proteins was analyzed by Western blot analysis. (C) The significance of AR in the GR gene regulation was tested by AR RNA interference (with small interfering RNA [siRNA]) in the cultured cells. C siRNA, control siRNA. (D) Luciferase assay was performed with a series of the GR promoter regions in AtT-20 cells. After transfection with each of the promoter tk-luciferase vectors, the transfected cells were incubated with or without 10−7 M DHT.
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