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Depression and obesity: evidence of shared biological mechanisms
Open accessAbstract
Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.
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The association between gut-health promoting diet and depression: A mediation analysis
Lai, C. C. W., & Boag, S. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.12.095 · Cited by 19
Yuan, F., Zhou, Z., Wu, S., Jiao, F., Chen, L., Fang, L., Yin, H., Hu, X., Jiang, X., Liu, K., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2215590120 · Cited by 19
Zhang, X., Wang, Y., Yang, X., Li, Y., Gui, J., Mei, Y., Liu, H., Guo, L.-L., Li, J., Lei, Y., et al. (2024) · BMC Psychiatry · doi:10.1186/s12888-024-05806-z · Cited by 20
Gerardo, G. M., Peterson, N. D., Goodpaster, K. P. S., & Heinberg, L. J. (2025) · Current Obesity Reports · doi:10.1007/s13679-024-00603-x · Cited by 17
“For additional review of the biological links of importance in this interaction, please see the works of groups lead by Milaneschi [21] and Schweinfurth [22].”
Gohar, S. M., Dieset, I., Steen, N. E., Mørch, R. H., Vedal, T. S. J., Reponen, E. J., Steen, V. M., Andreassen, O. A., & Melle, I. S. (2019) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.13019 · Cited by 20
“Furthermore, the interaction between adiposity and inflammation has been linked to leptin in several studies on depression (42).”
BackgroundKarabacak, D. E., Demir, S., Yeğit, O. O., Can, A., Terzioğlu, K., Ünal, D., Olgaç, M., Coşkun, R., Çolakoğlu, B., Büyüköztürk, S., et al. (2021) · Allergy · doi:10.1111/all.14796 · Cited by 19
Fried, E. I., & Haslbeck, J. M. B. (2018) · doi:10.31234/osf.io/84ske · Cited by 17
Seguella, L., Corpetti, C., Lu, J., Pesce, M., Franzin, S. B., Palenca, I., Zilli, A., Vincenzi, M., Caprioli, D., Paytuví-Gallart, A., et al. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.02.014 · Cited by 21
“Obesity-related metabolic diseases and long-term high-fat diets are associated with a high risk of developing depression-like behavior (Milaneschi et al., 2019) and psychiatric disorders (Martins et al., 2019), suggesting a direct linkage between diet-induced disease and “ mental health “ .”
Davoody, S., Halimi, H., Zali, A., Houri, H., & Brand, S. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107032 · Cited by 23
Schroeder, K., Dumenci, L., Sarwer, D. B., Noll, J. G., Henry, K., Suglia, S. F., Forke, C. M., & Wheeler, D. C. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19137819 · Cited by 19
“Mental health conditions resulting from ACEs exposure, including depression and binge eating disorder, also are risk factors for obesity [17,27,32,33].”
BackgroundKnight, E. L., Engeland, C. G., Yocum, A. K., Abu-Mohammad, A., Bertram, H. S., Vest, E., McInnis, M. G., & Saunders, E. F. H. (2023) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2023.100613 · Cited by 18
Relationship of perceived depression, stress, anxiety levels and hedonic hunger
Yalçın, T., Ayyıldız, F., Yılmaz, M. V., & Asil, E. (2023) · International Journal of Obesity · doi:10.1038/s41366-023-01315-3 · Cited by 18
“Studies have shown that depression, stress and anxiety are higher in people with obesity [42, 43].”
BackgroundMacho, S., Andrés, A., & Saldaña, C. (2023) · Obesity · doi:10.1002/oby.23802 · Cited by 19
“These results are not in line with previous research, especially those that found biological mechanisms explaining the relationship between depression and obesity [47].”
ResultAtasoy, S., Johar, H., Fang, X., Kruse, J., & Ladwig, K. (2018) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2018.10.007 · Cited by 18
“, it is thought that obesity causes inflammation related alterations in the insulin pathway that lead to T2DM (5).”
BackgroundReprint of: Recent Updates on Obesity Treatments: Available Drugs and Future Directions
Dragano, N. R. V., Fernø, J., Diéguez, C., López, M., & Milbank, E. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.08.009 · Cited by 18
Jang, H., & Oh, H. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18084162 · Cited by 18
Liang, K., Chen, S., & Chi, X. (2022) · Nutrients · doi:10.3390/nu14030524 · Cited by 18
“Although there is no consensus on the mechanisms that explain why skipping breakfast might harm mental health, a large number of studies have shown that skipping breakfast could increase the risk of obesity, which often occurs with mental health problems and may further increase the risk of mental health problems [34,…”
BackgroundKhidri, F. F., Riaz, H., Bhatti, U., Shahani, K. A., Ali, F. K., Effendi, S., Rani, K., & Chohan, M. N. (2022) · Psychology Research and Behavior Management · doi:10.2147/prbm.s364540 · Cited by 21
“Further research on the exploration of this relationship would help to find mechanisms and strategies for prevention and treatment.(32,33) The prevalence and risk ratio of depression increase with the presence of comorbidities and multiple chronic diseases(34) that has been found consistent with the findings of this s…”
ResultStudy of decreased serum levels of retinol binding protein 4 in major depressive disorder
Yao, Q., & Li, Y. (2020) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2020.05.030 · Cited by 16
Xiao, L., Zhou, J. L., Galling, B., Chen, R., & Wang, G. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.11.059 · Cited by 17
Zhou, Y., Yang, G., Peng, W., Zhang, H., Peng, Z., Ding, N., Guo, T., Cai, Y., Deng, Q., & Chai, X. (2020) · Behavioural Neurology · doi:10.1155/2020/9624106 · Cited by 17
“Weight status was related with the depression [32, 33].”
Hay, R., Cullen, B., Graham, N., Lyall, D. M., Aman, A., Pell, J. P., Ward, J., Smith, D. J., & Strawbridge, R. J. (2022) · European Journal of Human Genetics · doi:10.1038/s41431-022-01107-9 · Cited by 16
Zhang, C., Ma, W., Chen, Z., He, C., Zhang, Y., & Tao, Q. (2022) · Nutrients · doi:10.3390/nu14214508 · Cited by 21
“Obese adults have increased odds of depressive and anxiety symptoms compared with non-obese people [56,57].”
BackgroundWu, S., Chen, W.-J., Chang, J. P., Guu, T., Hsin, M.-C., Huang, C., Mischoulon, D., Capuron, L., & Su, K. (2023) · Journal of Personalized Medicine · doi:10.3390/jpm13061003 · Cited by 19
“Obesity and MDD share common mechanisms such as dysregulation of glucose and lipid metabolism, persistent inflammation, and excessive stimulation of the HPA axis [17,68].”
BackgroundLi, J., Zhang, J., Kong, B., Chen, L., Yuan, J., He, M., Wang, Y., Wei, S., Chen, W., Tang, Y., et al. (2023) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2023.111474 · Cited by 17
Kushner, R. F., Fink‐Jensen, A., Frenkel, O., McGowan, B. M., Goldman, B., Overvad, M., & Wadden, T. A. (2023) · Obesity · doi:10.1002/oby.23946 · Cited by 17
“These factors, in turn, can contribute to metabolic dysregulations and weight gain, resulting in a complex, mutually reinforcing cycle that links the two conditions [1, 2].”
BackgroundThe Co-occurrence of Depression and Obesity
McIntyre, R. S. (2024) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.24com15322 · Cited by 18
Matcha alleviates obesity by modulating gut microbiota and its metabolites
Luo, Y., Wen, Y., Huang, J., Chen, B., Lv, S., Qiu, H., Li, S., Liu, S., Yang, Q., He, L., et al. (2024) · Current Research in Food Science · doi:10.1016/j.crfs.2024.100823 · Cited by 19
Metadata
- Authors
- Milaneschi, Y., Simmons, W. K., van Rossum, E. F. C., & Penninx, B. W.
- Affiliations
- Amsterdam Neuroscience (NL)
- Laureate Institute for Brain Research (US)
- Corresponding author
- Penninx, Brenda WJH
- Venue
- Molecular Psychiatry
- Published
- 2018-02-16
- Volume
- 24
- Issue
- 1
- Pages
- 18-33
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2793219717
- Semantic Scholar
- 68e357daebf4d3c206fe34e3d98835cf2e71eb1c
- Cited by
- 1,073
- References
- 209
- Citations by year
- 2026: 128 · 2025: 216 · 2024: 180 · 2023: 181 · 2022: 147 · 2021: 108 · 2020: 59 · 2019: 44 · 2018: 9
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Social Sciences › Psychology › Clinical Psychology › Eating Disorders and Behaviors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- depression, obesity, bidirectional comorbidity, hypothalamic-pituitary-adrenal axis, inflammation, leptin, insulin, gut microbiota, energy metabolism, neuroendocrine regulation, brain circuits, genetic risk factors
- MeSH terms
- Brain, Depression, Major Depressive Disorder, Depressive Disorder, Energy Metabolism, Female, Homeostasis, Humans, Hypothalamo-Hypophyseal System, Inflammation, Insulin, Male, Obesity, Pituitary-Adrenal System, Leptin, Melanocortins, Microbiota
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