Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress

Biol Psychiatry. 2012 Sep 15;72(6):457-65. doi: 10.1016/j.biopsych.2012.03.010. Epub 2012 Apr 21.


Background: Ghrelin plays important roles in glucose metabolism, appetite, and body weight regulation, and recent evidence suggests ghrelin prevents excessive anxiety under conditions of chronic stress.

Methods: We used ghrelin knockout (ghr-/-) mice to examine the role of endogenous ghrelin in anxious behavior and hypothalamic-pituitary-adrenal axis (HPA) responses to acute stress.

Results: Ghr-/- mice are more anxious after acute restraint stress, compared with wild-type (WT) mice, with three independent behavioral tests. Acute restraint stress exacerbated neuronal activation in the hypothalamic paraventricular nucleus and medial nucleus of the amygdala in ghr-/- mice compared with WT, and exogenous ghrelin reversed this effect. Acute stress increased neuronal activation in the centrally projecting Edinger-Westphal nucleus in WT but not ghr-/- mice. Ghr-/- mice exhibited a lower corticosterone response after stress, suggesting dysfunctional glucocorticoid negative feedback in the absence of ghrelin. We found no differences in dexamethasone-induced Fos expression between ghr-/- and WT mice, suggesting central feedback was not impaired. Adrenocorticotropic hormone replacement elevated plasma corticosterone in ghr-/-, compared with WT mice, indicating increased adrenal sensitivity. The adrenocorticotropic hormone response to acute stress was significantly reduced in ghr-/- mice, compared with control subjects. Pro-opiomelanocortin anterior pituitary cells express significant growth hormone secretagogue receptor.

Conclusions: Ghrelin reduces anxiety after acute stress by stimulating the HPA axis at the level of the anterior pituitary. A novel neuronal growth hormone secretagogue receptor circuit involving urocortin 1 neurons in the centrally projecting Edinger-Westphal nucleus promotes an appropriate stress response. Thus, ghrelin regulates acute stress and offers potential therapeutic efficacy in human mood and stress disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adrenocorticotropic Hormone / metabolism*
  • Analysis of Variance
  • Animals
  • Anxiety / metabolism*
  • Corticosterone / blood
  • Corticosterone / metabolism
  • Corticotropin-Releasing Hormone / metabolism
  • Dexamethasone / pharmacology
  • Ghrelin / genetics
  • Ghrelin / physiology*
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiology*
  • Mice
  • Mice, Knockout
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / physiology*
  • Receptors, Ghrelin
  • Restraint, Physical
  • Stress, Psychological / physiopathology*


  • Ghrelin
  • Receptors, Ghrelin
  • Dexamethasone
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Corticosterone