A β3-Adrenergic-Leptin-Melanocortin Circuit Regulates Behavioral and Metabolic Changes Induced by Chronic Stress
Open accessAbstract
Background Obesity has been associated with an increased risk of developing several psychiatric illnesses, including major depression and posttraumatic stress disorder. Likewise, these stress-related disturbances are associated with a higher rate of obesity; yet, the neurobiological mechanisms linking obesity and stress remain incompletely understood. Methods Following exposure to chronic social defeat stress (CSDS), mice were given free access to either regular chow or a Western-style diet high in triglycerides and cholesterol. Comprehensive metabolic and behavioral testing was then conducted. Results Mice subjected to CSDS and then fed a high-fat diet for 30 days display severe behavioral deficits accompanied by redistribution of body fat. Stressed mice have decreased adipose tissue as well as decreased serum leptin levels compared with control mice. Pharmacological inhibition of beta(3)-adrenergic signaling during CSDS normalizes these metabolic abnormalities but worsens behavioral symptoms. Furthermore, mice subjected to CSDS display central leptin resistance including reduced expression of pro-opiomelanocortin in hypothalamus. Administration of a central melanocortin agonist worsens stress-induced behavioral deficits, while mice lacking the melanocortin-4 receptor display attenuated symptoms. Conclusions These results indicate that chronic signaling through beta(3)-adrenergic receptors during social stress is an adaptive response that improves behavioral function. However, these responses come at the expense of central leptin resistance and melanocortin signaling alterations that contribute to significant and long-lasting metabolic abnormalities.
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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 [25]
The Results section (page not available) links chronic social defeat stress to altered adipose tissue and leptin levels, supporting the lipid-regulation part of the claim. The Introduction mentions a prior finding about ghrelin and mood regulation, but this paper does not establish a link between susceptibility-related metabolic disturbances and alterations in orexin or ghrelin. (LLM, conf=0.85)
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- Authors
- Chuang, J.-C., Krishnan, V., Yu, H. G., Mason, B., Cui, H., Wilkinson, M. B., Zigman, J. M., Elmquist, J. K., Nestler, E. J., & Lutter, M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Lutter, Michael
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 67
- Issue
- 11
- Pages
- 1075-1082
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC2868111
- OpenAlex
- W1964530395
- Cited by
- 114
- References
- 3
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 12 · 2021: 1 · 2020: 4 · 2019: 11 · 2018: 8 · 2017: 5 · 2016: 5 · 2015: 10 · 2014: 10 · 2013: 11 · 2012: 6
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Alliance for Research in Schizophrenia and Depression (K08 MH084058-1A1, UL1-DE019584-02, R01 MH51399, R37 DK53301, R01DK071320, RL1 DK081182, 1RL1 DK081185-01, 1PL1DK081182-01, K08 DK068069-01A2, P50 MH066172)
- Sanofi-Aventis
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- chronic social defeat stress, beta3-adrenergic receptor, leptin resistance, melanocortin signaling, melanocortin-4 receptor, proopiomelanocortin, hypothalamus, high-fat diet, obesity, depression, post-traumatic stress disorder, fat redistribution, adipose tissue
- MeSH terms
- Adipose Tissue, Analysis of Variance, Animals, Body Composition, Enzyme-Linked Immunosorbent Assay, Hypothalamus, Male, Obesity, Social Behavior, Stress, Psychological, Blotting, Western, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Leptin, Receptors, Adrenergic, beta-3, Receptor, Melanocortin, Type 4, Mice, Melanocortins
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