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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Definition and diagnostic criteria of clinical obesity
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Self-citationStress and Obesity: Are There More Susceptible Individuals?
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Self-citationThe multiple roles of life stress in metabolic disorders
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“It could be that weight represents a major explanatory factor that accounts for the link between depression and inflammation, and that inflammation can occur in depressed patients because certain depressive symptoms emerge as a result from a shared pathophysiology with obesity and metabolic conditions (Lamers et al.,…”
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“As body mass index (BMI) has been shown to be associated with depression (4) and metabolites (42), we reran the main analyses adjusting for BMI.”
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“The reciprocal relationship between depression and systemic manifestations of low-grade chronic inflammation can form a vicious pathogenetic circle, strengthening each other [39, 40, 310–312].”
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“Medical comorbidity also contributes, including a bidirectional relationship between depression and obesity [96] that may be mediated through immune system activation and inflammation [96].”
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“IL-6 and CRP are synthesized in response to adipocytes within adipose tissue (43), and higher levels of body fat, in particular visceral fat, are related to metabolic inflammation and depression (44, 45).”
BackgroundGreen space exposure on depression and anxiety outcomes: A meta-analysis
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Self-citationObesity and psychological distress
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“The list of new theories and corresponding biomarkers with potential for predicting depression is expanding (e.g., Strawbridge et al., 2017; Milaneschi et al., 2019).”
BackgroundShared Genetic Loci Between Body Mass Index and Major Psychiatric Disorders
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“Alterations in metabolic, endocrine, and inflammatory processes likely represent mechanistic pathways underlying these associations (Figure 1) (14,63,64).”
BackgroundA comprehensive diagnostic approach to detect underlying causes of obesity in adults
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“Interestingly, obesity and depression show a robust association in epidemiological studies [33].”
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Self-citationDiet, Obesity, and Depression: A Systematic Review
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“Research has exposed metabolic and inflammatory dysregulation as a common denominator in depression and obesity [70,71].”
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“Obesity and insulin resistance, secondary to the excessive consumption of HFD, are events often associated with neuropsychiatric illnesses (Baker et al., 2017; Milaneschi et al., 2019; Tsan et al., 2021).”
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Self-citationThe Therapeutic Potential of Plant Polysaccharides in Metabolic Diseases
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Paeoniflorin: A neuroprotective monoterpenoid glycoside with promising anti-depressive properties
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Association Between Depression and Physical Conditions Requiring Hospitalization
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Delineating the Genetic Component of Gene Expression in Major Depression
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Depression and Obesity: Analysis of Common Biomarkers
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Prebiotic and Probiotic Modulation of the Microbiota–Gut–Brain Axis in Depression
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Inflammation and depression in young people: a systematic review and proposed inflammatory pathways
Toenders, Y. J., Laskaris, L., Davey, C. G., Berk, M., Milaneschi, Y., Lamers, F., Penninx, B. W. J. H., & Schmaal, L. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01306-8 · Cited by 98 · see citing works
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“The underlying mechanisms of obesity and depression can be explained by alterations in neuroendocrine regulation, activation of systemic immune inflammation, and emo - tionally modulated responses [44].”
Frank, P., Jokela, M. M., Batty, G. D., Lassale, C. M., Steptoe, A., & Mika Kivimaki, B. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.07.009 · Cited by 89 · see citing works
“inflammation and depression-related symptoms (Milaneschi et al., 2019; Speed et al., 2019).”
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“and depression have been closely linked(Milaneschi et al., 2019).”
Swainson, J., Reeson, M., Malik, U., Stefanuk, I., Cummins, M., & Sivapalan, S. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.01.094 · Cited by 87 · see citing works
Impact of the microbiome on human, animal, and environmental health from a One Health perspective
Ma, L., Zhao, H., Wu, L. B., Cheng, Z., & Liu, C. (2023) · Science in One Health · doi:10.1016/j.soh.2023.100037 · Cited by 86 · see citing works
“Additionally, the gut microbiome regulates ovarian dysfunction and insulin resistance in polycystic ovary syndrome [21], as well as participates in the neuroendocrine regulation associated with depression and obesity [22].”
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“Depression is reported to have a shared biological mechanism with obesity [93], which js influenced by food uptake and storage of energy that are known to be regulated by leptin.”
BackgroundUpdate on the Relationship Between Depression and Neuroendocrine Metabolism
Qiu, W., Cai, X., Zheng, C., Qiu, S., Ke, H., & Huang, Y. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.728810 · Cited by 86 · see citing works
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Maternal High-fat Diet Programs Offspring Emotional Behavior in Adulthood
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Eating Disorders: An Evolutionary Psychoneuroimmunological Approach
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“These results are consistent with the triggering effect on KP of inflammatory signals (Bonaccorso et al., 2002; Capuron et al., 2003), in particular of TNF (O’Connor et al., 2009; Robinson et al., 2005).”
Self-citationThe relationship between depressive symptoms and BMI: 2005–2018 NHANES data
He, K., Pang, T., & Huang, H. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.06.046 · Cited by 75 · see citing works
Shared biological mechanisms of depression and obesity: focus on adipokines and lipokines
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Recent Updates on Obesity Treatments: Available Drugs and Future Directions
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The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives
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Maternal depression and inflammation during pregnancy
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Associations between depression, lifestyle and brain structure: A longitudinal MRI study
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Self-citationDepression and Cardiovascular Disease: The Viewpoint of Platelets
Amadio, P., Zarà, M., Sandrini, L., Ieraci, A., & Barbieri, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207560 · Cited by 65 · see citing works
“Neuroendocrine regulators of energy metabolism are crucial in determining cardiovascular risk [70], and are associated with depression disorders [71].”
BackgroundLengton, R., Schoenmakers, M., Penninx, B. W. J. H., Boon, M. R., & van Rossum, E. F. C. (2024) · Clinical Obesity · doi:10.1111/cob.12725 · Cited by 68 · see citing works
“12,29,78 Chronic inflammation, next to long-term stress, has been associated with increased risk of various diseases, such as infectious illnesses, cardiovascular disease, diabetes, obesity, certain cancers and autoimmune disease, as well as a decline in overall health and higher mortality rates.”
InfluentialSelf-citationSobolewska-Nowak, J., Wachowska, K., Nowak, A., Orzechowska, A., Szulc, A., Płaza, O., & Gałecki, P. (2023) · Biomedicines · doi:10.3390/biomedicines11071903 · Cited by 72 · see citing works
“Excessive body weight, particularly when it is characterized by excess fat accumulation, places strain on the cardiovascular system and increases the likelihood of developing various cardiovascular conditions [31,41].”
BackgroundResultBrain-immune crosstalk in the treatment of major depressive disorder
Branchi, I., Poggini, S., Capuron, L., Benedetti, F., Poletti, S., Tamouza, R., Drexhage, H. A., Penninx, B. W. J. H., & Pariante, C. M. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.11.016 · Cited by 64 · see citing works
Self-citationGuirguis, A., Chiappini, S., P, G. P., Vickers‐Smith, R., Harris, D. R., Corkery, J., Arillotta, D., Floresta, G., Martinotti, G., & Schifano, F. (2024) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2024.02.003 · Cited by 70 · see citing works
“Additionally, psychological factors like un-healthy coping mechanisms may play a role in the development and maintenance of obesity whilst also possibly impacting on mental health (Milaneschi et al., 2019; Lopresti and Drummond, 2013).”
BackgroundDreimüller, N., Lieb, K., Tadić, A., Engelmann, J., Wollschläger, D., & Wagner, S. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.06.067 · Cited by 64 · see citing works
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“MDD include (1) mood reactivity and at least two of the following four symptoms: (2) increase in appetite or significant weight gain, (3) hypersomnia, (4) leaden paralysis, and (5) interpersonal rejection sensitivity.”
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“It is one of the most severe metabolic disorder conditions, which generally develop due to improper energy intake versus energy workout [3–7], stress [8], sedentary lifestyle [9], alcohol consumption [10], depression [11], insufficient nutritional knowledge about the food supplements, and then, ultimately these leads…”
BackgroundMood‐related central and peripheral clocks
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The relationship between depression and relative fat mass (RFM): A population-based study
Zhu, X., Yue, Y., Li, L., Zhu, L., Cai, Y., & Shu, Y. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.04.031 · Cited by 59 · see citing works
Bariatric surgery and health outcomes: An umbrella analysis
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“But psychiatric diseases also seem to share some pathophysiological brain pathways in common with those leading to weight gain and its metabolic complications, thereby creating a kind of vicious circle where each of the pathways influences the risk for the other [21].”
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The metabolome-wide signature of major depressive disorder
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“Such fi ndings not only indicate pathway dysregulations that contribute to depression symptomatology development-but also help explain why comorbidities like metabolic syndrome [4], obesity [5], diabetes [6]) and cardiovascular disease [7] occur more often in depressed than non-depressed persons.”
Self-citationThe microbiota: a key regulator of health, productivity, and reproductive success in mammals
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Childhood overweight and obesity and the risk of depression across the lifespan
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“, altered sleep and increased fatigue) in ways that are bidirectional and mutually-reinforcing (Luppino et al., 2010; Milaneschi et al., 2019).”
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Astrocytes in Post-traumatic Stress Disorder
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“Generally, therapeutic strategies are aimed at neurons (monoamine hypothesis [156], hypercortisolism hypothesis [157], BDNF hypothesis [158], and myo-inositol hypothesis [159]).”
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Auricular transcutaneous vagus nerve stimulation modulates the heart-evoked potential
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“An ever increasing body of evidence reports that systems involved in homeostatic adjustments such as the neuroendocrine, the immuno-inflammatory and the energy metabolism (insulin and leptin) are greatly altered both in psychiatric and metabolic disorders (Milaneschi et al., 2019).”
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“The adipose-derived hormone leptin is well known for its function in controlling energy homeostasis and has been recently involved in regulating mood and emotion [59, 60].”
Nucleus accumbens melanin-concentrating hormone signaling promotes feeding in a sex-specific manner
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- 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 › Epidemiology › 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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