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

Sarah J. Spencer, Lu Xu, Melanie A. Clarke, Moyra Lemus, Alex Reichenbach, Bram Geenen, Tamas Kozicz, Zane B. Andrews

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)457-465
Number of pages9
JournalBiological Psychiatry
Volume72
Issue number6
DOIs
StatePublished - Sep 15 2012
Externally publishedYes

Fingerprint

Ghrelin
Anxiety
Ghrelin Receptor
Corticosterone
Adrenocorticotropic Hormone
Urocortins
Pro-Opiomelanocortin
Paraventricular Hypothalamic Nucleus
Appetite
Mood Disorders
Knockout Mice
Dexamethasone
Glucocorticoids
Body Weight
Neurons
Glucose

Keywords

  • Anxiety
  • depression
  • ghrelin
  • hypothalamic-pituitary-adrenal axis
  • knockout
  • stress

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Spencer, S. J., Xu, L., Clarke, M. A., Lemus, M., Reichenbach, A., Geenen, B., ... Andrews, Z. B. (2012). Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biological Psychiatry, 72(6), 457-465. https://doi.org/10.1016/j.biopsych.2012.03.010

Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. / Spencer, Sarah J.; Xu, Lu; Clarke, Melanie A.; Lemus, Moyra; Reichenbach, Alex; Geenen, Bram; Kozicz, Tamas; Andrews, Zane B.

In: Biological Psychiatry, Vol. 72, No. 6, 15.09.2012, p. 457-465.

Research output: Contribution to journalArticle

Spencer, SJ, Xu, L, Clarke, MA, Lemus, M, Reichenbach, A, Geenen, B, Kozicz, T & Andrews, ZB 2012, 'Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress', Biological Psychiatry, vol. 72, no. 6, pp. 457-465. https://doi.org/10.1016/j.biopsych.2012.03.010
Spencer, Sarah J. ; Xu, Lu ; Clarke, Melanie A. ; Lemus, Moyra ; Reichenbach, Alex ; Geenen, Bram ; Kozicz, Tamas ; Andrews, Zane B. / Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. In: Biological Psychiatry. 2012 ; Vol. 72, No. 6. pp. 457-465.
@article{1f9dd35824b44e3a94422db59e4cebc2,
title = "Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress",
abstract = "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. 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. 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. 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.",
keywords = "Anxiety, depression, ghrelin, hypothalamic-pituitary-adrenal axis, knockout, stress",
author = "Spencer, {Sarah J.} and Lu Xu and Clarke, {Melanie A.} and Moyra Lemus and Alex Reichenbach and Bram Geenen and Tamas Kozicz and Andrews, {Zane B.}",
year = "2012",
month = "9",
day = "15",
doi = "10.1016/j.biopsych.2012.03.010",
language = "English (US)",
volume = "72",
pages = "457--465",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "6",

}

TY - JOUR

T1 - Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress

AU - Spencer, Sarah J.

AU - Xu, Lu

AU - Clarke, Melanie A.

AU - Lemus, Moyra

AU - Reichenbach, Alex

AU - Geenen, Bram

AU - Kozicz, Tamas

AU - Andrews, Zane B.

PY - 2012/9/15

Y1 - 2012/9/15

N2 - 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. 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. 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. 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.

AB - 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. 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. 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. 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.

KW - Anxiety

KW - depression

KW - ghrelin

KW - hypothalamic-pituitary-adrenal axis

KW - knockout

KW - stress

UR - http://www.scopus.com/inward/record.url?scp=84865205876&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865205876&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2012.03.010

DO - 10.1016/j.biopsych.2012.03.010

M3 - Article

C2 - 22521145

AN - SCOPUS:84865205876

VL - 72

SP - 457

EP - 465

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 6

ER -