The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress
Open accessAbstract
We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic- and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin levels, whereas growth hormone secretagogue receptor (Ghsr) null mice showed increased deleterious effects of chronic defeat. Together, these findings demonstrate a previously unknown function for ghrelin in defending against depressive-like symptoms of chronic stress.
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The metabolic disturbances associated with susceptibility have been linked to alterations in orexin, ghrelin and lipid regulation.
“Interestingly, the metabolic disturbances associated with susceptibility have been linked to alterations in orexin, ghrelin and lipid regulation23–26.”
From A standardized protocol for repeated social defeat stress in mice (2011) · cites this paper as [23]
About 35% of stressed C57BL6/J mice are resilient and do not show social avoidance, social-interaction hyperthermia, anhedonia-like symptoms, or metabolic syndrome.
“~35% of the stressed mice, considered “resilient,” do not exhibit social avoidance, hyperthermia elicited by social interactions, anhedonia–like symptoms (reduced interest in sucrose, high fat food, or sex), or a metabolic syndrome characterized by over–eating, obesity, and central leptin resistance24, 28.”
From Neurobiology of resilience (2012) · cites this paper as [28]
The group defined resilience to chronic social defeat stress as absence of social avoidance, anhedonia, and metabolic syndrome, which are highly correlated.
“Our group has defined resilience to chronic social defeat stress as the absence of social avoidance, anhedonia, and metabolic syndrome, which are highly correlated with one another24, 27, 28, 36.”
From Neurobiology of resilience (2012) · cites this paper as [28]
Mice lacking GHS receptors are more susceptible to stress and exhibit anxiety- and depressive-like behavior.
“Moreover, mice lacking growth hormone secretagogue (GHS) receptors are more susceptible to stress and exhibit anxiety-and depressive-like behavior [309,312].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [309]
Different stressors such as social defeat and restraint stress in rodents can increase long-term ghrelin levels in stomach.
“However, different stressors, such as social defeat and restraint stress in rodents, can increase long-term ghrelin levels in the stomach [309][310][311].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [309]
Chronically elevated plasma ghrelin, associated with changes in gut microbiota, can prevent anxiety- and depression-like behavior through ghrelin receptors.
“In addition, chronically elevated plasma ghrelin, associated with changes in the gut microbiota, can prevent anxiety-and depression-like behavior through ghrelin receptors [309].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [309]
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- Authors
- 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., & Zigman, J. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zigman, Jeffrey M
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2008-06-15
- Volume
- 11
- Issue
- 7
- Pages
- 752-753
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2765052
- OpenAlex
- W2067273260
- Cited by
- 644
- References
- 12
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 29 · 2023: 28 · 2022: 35 · 2021: 33 · 2020: 27 · 2019: 34 · 2018: 39 · 2017: 45 · 2016: 41 · 2015: 44 · 2014: 45 · 2013: 52 · 2012: 44
- FWCI
- 15.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (P50 MH66172, P50MH066172)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK56116, PL1DK081182, RL1DK081185, P01DK056116, R01DK071320, K08DK068069, R01-DK-71320)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- ghrelin, depression, chronic stress, social defeat stress, anxiolytic effects, antidepressant effects, caloric restriction, growth hormone secretagogue receptor, elevated plus maze, forced swim test, orexigenic hormones
- MeSH terms
- Analysis of Variance, Animals, Behavior, Animal, Depression, Disease Models, Animal, Eating, Enzyme-Linked Immunosorbent Assay, Mice, Inbred C57BL, Motor Activity, Reaction Time, Stress, Psychological, Swimming, Time Factors, Receptors, Neuropeptide, Mice, Knockout, Maze Learning, Caloric Restriction, Receptors, G-Protein-Coupled, Freezing Reaction, Cataleptic, Mice, Ghrelin, Receptors, Ghrelin, Orexin Receptors
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