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

JCI Insight. 2018 Oct 4;3(19):e122932. doi: 10.1172/jci.insight.122932.

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.

Keywords: Endocrinology; Neuroendocrine regulation; growth factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Insufficiency / etiology*
  • Adrenal Insufficiency / physiopathology
  • Adrenocorticotropic Hormone / metabolism
  • Animals
  • Cell Line, Tumor
  • Corticosterone / metabolism
  • Corticotrophs / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Humans
  • Hypothalamo-Hypophyseal System / cytology
  • Hypothalamo-Hypophyseal System / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / metabolism*
  • Pituitary-Adrenal System / cytology
  • Pituitary-Adrenal System / physiology*
  • Receptors, Corticotropin-Releasing Hormone / genetics*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Receptors, Somatostatin / genetics
  • Receptors, Somatostatin / metabolism*
  • Stress, Psychological / complications*
  • Stress, Psychological / physiopathology

Substances

  • MicroRNAs
  • Mirn449 microRNA, mouse
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Somatostatin
  • CRF receptor type 1
  • somatostatin receptor 5
  • Adrenocorticotropic Hormone
  • Corticosterone