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Ghrelin Regulates the Hypothalamic-Pituitary-Adrenal Axis and Restricts Anxiety After Acute Stress
Open accessAbstract
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.
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“Ghrelin is a 28 amino-acid stomach-derived peptide known for its powerful physiological orexigenic and adipogenic effects, as well as for its contribution toward the stress response, anxiety, and depression [293][294][295][296][297].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [295]
In the citing paper
“Mice lacking endogenous ghrelin have a dampened circulating glucocorticoid response following an acute stressor due a deficit in the PVN response needed to stimulate ACTH from the pituitary [295,311].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [295]
Citations
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190
Stress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621
Ghrelin induces adiposity in rodents
Tschöp, M., Smiley, D. L., & Heiman, M. L. (2000) · Nature · doi:10.1038/35038090 · Cited by 3,949
Joëls, M., & Baram, T. Z. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2632 · Cited by 1,521
Expression of ghrelin receptor mRNA in the rat and the mouse brain
Zigman, J. M., Jones, J. E., Lee, C. E., Saper, C. B., & Elmquist, J. K. (2006) · The Journal of Comparative Neurology · doi:10.1002/cne.20823 · Cited by 1,074
The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress
Lutter, M., Sakata, I., Osborne-Lawrence, S., Rovinsky, S. A., Anderson, J. G., Jung, S., Birnbaum, S., Yanagisawa, M., Elmquist, J. K., Nestler, E. J., et al. (2008) · Nature Neuroscience · doi:10.1038/nn.2139 · Cited by 644
Dayas, C. V., Buller, K. M., Crane, J. W., Xu, Y., & Day, T. A. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01733.x · Cited by 514
Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference
Wortley, K. E., Anderson, K. D., García, K., Murray, J. D., Malinova, L., Liu, R., Moncrieffe, M., Thabet, K., Cox, H. J., Yancopoulos, G. D., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402763101 · Cited by 473
Ghrelin increases anxiety-like behavior and memory retention in rats
Carlini, V. P., Monzon, M. E., Varas, M., Cragnolini, A. B., Schiöth, H. B., Scimonelli, T. N., & de Barioglio, S. R. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02740-7 · Cited by 373
Bittencourt, J. C., Vaughan, J. M., Arias, C., Rissman, R. A., Vale, W., & Sawchenko, P. E. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19991220)415:3 · Cited by 367
A Role of Ghrelin in Neuroendocrine and Behavioral Responses to Stress in Mice
Asakawa, A., Inui, A., Kaga, T., Yuzuriha, H., Nagata, T., Fujimiya, M., Katsuura, G., Makino, S., Fujino, M., & Kasuga, M. (2001) · Neuroendocrinology · doi:10.1159/000054680 · Cited by 363
PRECLINICAL STUDY: FULL ARTICLE: Ghrelin increases intake of rewarding food in rodents
Egecioglu, E., Jerlhag, E., Salomé, N., Skibicka, K. P., Haage, D., Bohlooly‐Y, M., Andersson, D. R., Bjursell, M., Perrissoud, D., Engel, J. A., et al. (2010) · Addiction Biology · doi:10.1111/j.1369-1600.2010.00216.x · Cited by 351
Ghrelin mediates stress-induced food-reward behavior in mice
Chuang, J.-C., Perelló, M., Sakata, I., Osborne-Lawrence, S. L., Savitt, J. M., Lutter, M. L., & Zigman, J. M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57660 · Cited by 347
Carlini, V., Varas, M., Cragnolini, A., Schiöth, H., Scimonelli, T., & Debarioglio, S. R. (2004) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2003.11.150 · Cited by 347
Diet-Induced Obesity Causes Ghrelin Resistance in Arcuate NPY/AgRP Neurons
Briggs, D. I., Enriori, P. J., Lemus, M. B., Cowley, M. A., & Andrews, Z. B. (2010) · Endocrinology · doi:10.1210/en.2010-0556 · Cited by 320
Self-citationDayas, C. V., Buller, K. M., & Day, T. A. (1999) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1999.00645.x · Cited by 303
Andrews, Z. B., Erion, D., Beiler, R., Liu, Z.-W., Abizaid, A., Zigman, J., Elsworth, J. D., Savitt, J. M., DiMarchi, R., Tschöp, M., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3890-09.2009 · Cited by 289
Kalueff, A., & Tuohimaa, P. (2005) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.10.001 · Cited by 284
Kozicz, T., Bittencourt, J. C., May, P. J., Reiner, A. J., Gamlin, P. D., Palkovits, M., Horn, A. K. E., Toledo, C. A. B., & Ryabinin, A. E. (2010) · The Journal of Comparative Neurology · doi:10.1002/cne.22580 · Cited by 204
The extra-hypothalamic actions of ghrelin on neuronal function
Andrews, Z. B. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.10.001 · Cited by 199
Acute psychological stress raises plasma ghrelin in the rat
Kristenssson, E., Sundqvist, M., Astin, M., Kjerling, M., Mattsson, H., de la Cour, C. D., Håkanson, R., & Lindström, E. (2006) · Regulatory Peptides · doi:10.1016/j.regpep.2006.02.003 · Cited by 179
Spencer, S. J., Buller, K. M., & Day, T. A. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.20376 · Cited by 171
Rouach, V., Bloch, M., Rosenberg, N., Gilad, S., Limor, R., Stern, N., & Greenman, Y. (2007) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2007.04.010 · Cited by 159
Viau, V., & Sawchenko, P. E. (2002) · The Journal of Comparative Neurology · doi:10.1002/cne.10178 · Cited by 153
Weninger, S. C., Peters, L. L., & Majzoub, J. A. (2000) · Endocrinology · doi:10.1210/endo.141.1.7277 · Cited by 149
Lantéri‐Minet, M., Isnardon, P., de Pommery, J., & Menétrey, D. (1993) · Neuroscience · doi:10.1016/0306-4522(93)90439-m · Cited by 147
Onaivi, E. S., & Martin, B. R. (1989) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/0278-5846(89)90047-x · Cited by 133
In vivo characterization of high Basal signaling from the ghrelin receptor
Petersen, P. S., Woldbye, D. P. D., Madsen, A. N., Egerod, K. L., Jin, C., Lang, M., Rasmussen, M., Beck-Sickinger, A. G., & Holst, B. (2009) · Endocrinology · doi:10.1210/en.2008-1638 · Cited by 121
Effects of repeated restraint stress on gastric motility in rats
Zheng, J., Dobner, A., Babygirija, R., Ludwig, K., & Takahashi, T. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90928.2008 · Cited by 119
Galic, M. A., Riazi, K., Henderson, A. K., Tsutsui, S., & Pittman, Q. J. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.07.025 · Cited by 117
Glazner, G. W., Mu, X., & Springer, J. E. (1998) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19980202)391:1 · Cited by 110
Early life immune challenge—effects on behavioural indices of adult rat fear and anxiety
Spencer, S. J., Heida, J. G., & Pittman, Q. J. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2005.06.032 · Cited by 109
Gaszner, B., CSERNUS, V. J., & Kozicz, T. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.20343 · Cited by 106
Linden, A.-M., Greene, S. J., Bergeron, M., & Schoepp, D. D. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300321 · Cited by 106
Barim, A. Ö., Aydın, S., Çolak, R., Dağ, E., Deniz, O., & Şahin, İ. (2009) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2009.02.020 · Cited by 103
Schmidt, M. V., Levine, S. D., Alam, S., Harbich, D., Sterlemann, V., Ganea, K., de Kloet, E. R., Holsboer, F., & Müller, M. B. (2006) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2006.01482.x · Cited by 93
On the role of urocortin 1 in the non-preganglionic Edinger–Westphal nucleus in stress adaptation
Kozicz, T. (2007) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2007.04.005 · Cited by 92
Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways
Mouihate, A., Galic, M. A., Ellis, S. L., Spencer, S. J., Tsutsui, S., & Pittman, Q. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.6078-09.2010 · Cited by 87
Neonatal overfeeding alters adult anxiety and stress responsiveness
Spencer, S. J., & Tilbrook, A. J. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.02.013 · Cited by 82
Ghrelin gene polymorphism is associated with depression, but not panic disorder
Nakashima, K., Akiyoshi, J., Hatano, K., Hanada, H., Tanaka, Y., Tsuru, J., Matsushita, H., Kodama, K., & Isogawa, K. (2008) · Psychiatric Genetics · doi:10.1097/ypg.0b013e328306c979 · Cited by 60
Enthoven, L., Oitzl, M. S., Koning, N. R., van der Mark, M. H., & de Kloet, E. R. (2008) · Endocrinology · doi:10.1210/en.2008-0238 · Cited by 60
Kozicz, T., Li, M., & Areviura, A. (2001) · Stress · doi:10.3109/10253890109115724 · Cited by 58
Rouwette, T., Klemann, C. J. H. M., Gaszner, B., Scheffer, G. J., Roubos, E. W., Scheenen, W. J. J. M., Vissers, K. C. P., & Kozicz, T. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.03.054 · Cited by 57
Clarke, M. A., Stefanidis, A., & Spencer, S. J. (2011) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02269.x · Cited by 55
Linden, A.-M., Baez, M., Bergeron, M., & Schoepp, D. D. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.03.014 · Cited by 46
Leptin inhibits and ghrelin augments hypothalamic noradrenaline release after stress
Kawakami, A., Kawakami, A., Okada, N., Rokkaku, K., Honda, K., Ishibashi, S., & Onaka, T. (2008) · Stress · doi:10.1080/10253890701820257 · Cited by 43
Neuronal activation in the CNS during different forms of acute renal failure in rats
Palkovits, M., Šebeková, K., Gallatz, K., Boor, P., Šebeková, K., Klassen, A., Bahner, U., & Heidland, A. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2008.12.062 · Cited by 36
Plasma leptin and ghrelin in the neonatal rat: interaction of dexamethasone and hypoxia
Bruder, E. D., Jacobson, L., & Raff, H. (2005) · Journal of Endocrinology · doi:10.1677/joe.1.06159 · Cited by 33
Does midbrain urocortin 1 matter? A 15-year journey from stress (mal)adaptation to energy metabolism
Kozicz, T., Sterrenburg, L., & Xu, L. (2011) · Stress · doi:10.3109/10253890.2011.563806 · Cited by 28
Bulfin, L., Clarke, M. A., Buller, K. M., & Spencer, S. J. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.01.006 · Cited by 28
Skelton, K. H., Nemeroff, C. B., & Owens, M. J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1737-04.2004 · Cited by 23
Ghrelin: from a GH-secretagogue to the regulation of food intake, sleep and anxiety.
Seoane, L. M., Al–Massadi, O., Lage, M., Diéguez, C., & Casanueva, F. F. (2004) · PubMed · Cited by 15
Zhao, Y., Shao, L., Teng, L., Zhang, D., & Zhang, H. (2010) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/s11596-010-0347-2 · Cited by 5
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Self-citationAnxiety, depression, and the microbiome: A role for gut peptides
Lach, G., Schellekens, H., Dinan, T. G., & Cryan, J. F. (2018) · Neurotherapeutics · doi:10.1007/s13311-017-0585-0 · Cited by 573
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McClung, C. A. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.02.019 · Cited by 507
“Moreover, ghrelin (Ghr −/−) knock-out mice are more anxious after acute restraint stress and this is likely due to a problem with the normal glucocorticoid feedback in response to stress (68).”
BackgroundDiet, Stress and Mental Health
Bremner, J. D., Moazzami, K., Wittbrodt, M. T., Nye, J. A., Lima, B. B., Gillespie, C. F., Rapaport, M. H., Pearce, B. D., Shah, A. J., & Vaccarino, V. (2020) · Nutrients · doi:10.3390/nu12082428 · Cited by 421
“Stress increases ghrelin levels in the plasma [218,219], and ghrelin mediates the stress-induced increase in food intake associated with exposure to chronic stress [220] as well as behavioral responses to stress [219].”
BackgroundEating behavior and stress: a pathway to obesity
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“…(Kristenssson et al., 2006) and probably acts at the level of the anterior pituitary as well as higher brain regions, such as the centrally projecting Edinger Westphal nucleus (EWcp), to modulate ACTH release from the pituitary and regulate glucocorticoid negative feedback (Spencer et al., 2012).”
Background
Metadata
- Authors
- Spencer, S. J., Xu, L., Clarke, M. A., Lemus, M., Reichenbach, A., Geenen, B., Kozicz, T., & Andrews, Z. B.
- Affiliations
- Monash University (AU)
- Radboud University Nijmegen (NL)
- Corresponding author
- Andrews, Zane B.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 72
- Issue
- 6
- Pages
- 457-465
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2068804599
- Cited by
- 241
- References
- 54
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 23 · 2023: 11 · 2022: 15 · 2021: 20 · 2020: 15 · 2019: 16 · 2018: 13 · 2017: 23 · 2016: 22 · 2015: 16 · 2014: 21 · 2013: 22 · 2012: 4
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Licence
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Health and Medical Research Council of Australia (1011274)
- Australian Research Council (DP109339)
- Monash Fellowship (FT100100966)
- National Health and Medical Research Council Peter Doherty Research Fellowship (465167)
- Endocrine Society of Australia Postdoctoral Fellowship (FT110100084)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- ghrelin, hypothalamic-pituitary-adrenal axis, anxiety, acute stress, restraint stress, corticosterone, glucocorticoid negative feedback, ACTH, anterior pituitary, growth hormone secretagogue receptor, proopiomelanocortin, Edinger-Westphal nucleus, urocortin 1, paraventricular nucleus, amygdala, stress response
- MeSH terms
- Adrenocorticotropic Hormone, Analysis of Variance, Animals, Anxiety, Corticosterone, Corticotropin-Releasing Hormone, Dexamethasone, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Restraint, Physical, Stress, Psychological, Mice, Knockout, Mice, Ghrelin, Receptors, Ghrelin
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