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Somatostatin receptor subtype 5 modifies hypothalamic-pituitary-adrenal axis stress function
Masaaki Yamamoto, … , Yan Ding, Shlomo Melmed
Masaaki Yamamoto, … , Yan Ding, Shlomo Melmed
Published October 4, 2018
Citation Information: JCI Insight. 2018;3(19):e122932. https://doi.org/10.1172/jci.insight.122932.
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Research Article Endocrinology

Somatostatin receptor subtype 5 modifies hypothalamic-pituitary-adrenal axis stress function

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Abstract

Pituitary corticotroph somatostatin receptor subtype 5 (SSTR5) signals to inhibit adrenocorticotrophin (ACTH) secretion. As ACTH deficiency results in attenuated adrenal cortisol production and an impaired stress response, we sought to clarify the role of SSTR5 in modifying the hypothalamic/pituitary/adrenal (HPA) axis. We generated Tg HP5 mice overexpressing SSTR5 in pituitary corticotrophs that produce the ACTH precursor proopiomelanocortin (POMC). Basal ACTH and corticosterone were similar in HP5 and WT mice, while HP5 mice showed attenuated ACTH and corticosterone responses to corticotrophin releasing hormone (CRH). HP5 mice exhibited attenuated corticosterone responses upon a restraint stress test and inflammatory stress following LPS injection, as well as increased anxiety-like and depressive-like behavior on open field and forced swim tests. Pituitary corticotroph CRH receptor subtype 1 (CRHR1) mRNA expression and ACTH responses to CRH were also attenuated in HP5 mice. In AtT20 cells stably overexpressing SSTR5, CRHR1 expression and cAMP response to CRH were reduced, whereas both were increased after SSTR5 KO. In elucidating mechanisms for these observations, we show that SSTR5-induced miR-449c suppresses both CRHR1 expression and function. We conclude that corticotroph SSTR5 attenuates HPA axis responses via CRHR1 downregulation, suggesting a role for SSTR5 in the pathogenesis of secondary adrenal insufficiency.

Authors

Masaaki Yamamoto, Anat Ben-Shlomo, Hiraku Kameda, Hidenori Fukuoka, Nan Deng, Yan Ding, Shlomo Melmed

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Figure 1

Morphologic characterization of HP5 transgenic mice.

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Morphologic characterization of HP5 transgenic mice.
(A) Construct map o...
(A) Construct map of rat Pomc-enhancer-neuroD1-Tpit/Pitx1 (PENT) promoter with HA-tagged human SSTR5 gene (33). (B) Western blot analysis of HA-hSSTR5 expression in whole-cell extracts derived from the hypothalamus, pituitary, and adrenal glands of WT and HP5 mice. Anti-HA antibody was used to detect hSSTR5, and Ponceau S staining served as the loading control. (C–E) Immunofluorescent staining of (C) WT and (D) HP5 pituitary; rectangle in D is enlarged and shown in E using anti-DAPI, anti-hSSTR5, and anti-POMC; merged image is also depicted. Staining was analyzed by confocal microscopy. Scale bars: 500 μm in C and 200 μm in D. AL, anterior lobe; IL, intermediate lobe; PL, posterior lobe.

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