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Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress.
Biol Psychiatry 2012; 72(6):457-65BP

Abstract

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.

Authors+Show Affiliations

Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22521145

Citation

Spencer, Sarah J., et al. "Ghrelin Regulates the Hypothalamic-pituitary-adrenal Axis and Restricts Anxiety After Acute Stress." Biological Psychiatry, vol. 72, no. 6, 2012, pp. 457-65.
Spencer SJ, Xu L, Clarke MA, et al. Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol Psychiatry. 2012;72(6):457-65.
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), pp. 457-65. doi:10.1016/j.biopsych.2012.03.010.
Spencer SJ, et al. Ghrelin Regulates the Hypothalamic-pituitary-adrenal Axis and Restricts Anxiety After Acute Stress. Biol Psychiatry. 2012 Sep 15;72(6):457-65. PubMed PMID: 22521145.
* Article titles in AMA citation format should be in sentence-case
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,Tamás, AU - Andrews,Zane B, Y1 - 2012/04/21/ PY - 2011/12/13/received PY - 2012/03/05/revised PY - 2012/03/05/accepted PY - 2012/4/24/entrez PY - 2012/4/24/pubmed PY - 2013/1/23/medline SP - 457 EP - 65 JF - Biological psychiatry JO - Biol. Psychiatry VL - 72 IS - 6 N2 - 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. SN - 1873-2402 UR - https://www.unboundmedicine.com/medline/citation/22521145/Ghrelin_regulates_the_hypothalamic_pituitary_adrenal_axis_and_restricts_anxiety_after_acute_stress_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(12)00237-5 DB - PRIME DP - Unbound Medicine ER -