Cited by 1,073Regulation of Appetite and ObesityEating Disorders and BehaviorsAdipokines, Inflammation, and Metabolic Diseases

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Depression and obesity: evidence of shared biological mechanisms

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Milaneschi, Yuri, Simmons, W. Kyle, van Rossum, Elisabeth F. C., Penninx, Brenda WJH·2019·Molecular Psychiatry

DOI 10.1038/s41380-018-0017-5

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Abstract

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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Drożak, P., Duda, P., Bryliński, Ł., Augustowska, K., Drożak, M., Bura, A., & Rudnicka-Drożak, E. (2021) · Journal of Education Health and Sport · doi:10.12775/jehs.2021.11.07.014 · Cited by 5
Neural correlates of verbal recognition memory in obese adults with and without major depressive disorder
Restivo, M. R., Hall, G. B., Frey, B. N., McKinnon, M. C., & Taylor, V. H. (2020) · Brain and Behavior · doi:10.1002/brb3.1848 · Cited by 4
MDepressionKG
Fu, C., Jiang, X., He, T., & Jiang, X. (2021) · International Symposium on Artificial Intelligence for Medicine Sciences (ISAIMS) · doi:10.1145/3500931.3500944 · Cited by 6
“For instance, studies in recent years have shown that human chronic diseases such as diabetes, irritable bowel syndrome, cardiovascular disease, and obesity are closely related to the occurrence of depression disorder [7-10].”
Background
A qualitative investigation of the need for and feasibility of weight loss programs on university campuses
Bennett, M., Whiteley, J. A., Gu, J., Gaminian, A., & Napolitano, M. A. (2022) · Obesity Research & Clinical Practice · doi:10.1016/j.orcp.2021.11.003 · Cited by 5
Behavioral health disorders related to nonalcoholic steatohepatitis
Sharma, A., Albhaisi, S. A. M., & Sanyal, A. J. (2022) · Clinical Liver Disease · doi:10.1002/cld.1211 · Cited by 5
Harnessing the Power of Population Cohorts to Study the Relationship Between Endocrine-Metabolic Disorders and Depression
Jespersen, A., Yılmaz, Z., & Vilhjálmsson, B. J. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20220798 · Cited by 5
Prevalence of use and interest in using glucagon-like peptide-1 receptor agonists for weight loss: a population study in Great BritainPreprint
Jackson, S. E., Brown, J., Llewellyn, C. H., Mytton, O. T., & Shahab, L. (2025) · medRxiv · doi:10.1101/2025.06.06.25329114 · Cited by 5
Causal Relationship Between Depression and Traumatic Brain Injury: A Two‐Sample Mendelian Randomization Analysis
Wang, S., Pan, L., Wang, B. H., Ruan, Q., Shi, Y., Sun, T., Yang, X., Zhang, L., Ke, X., Li, G., et al. (2025) · Brain and Behavior · doi:10.1002/brb3.70669 · Cited by 4
“Epidemiological studies have shown significant comorbidity with hypertension (Cai et al. 2022), insomnia (Riemann et al. 2020), diabetes mellitus (Basiri et al. 2023), cardiovascular diseases (El-Battrawy et al. 2021), cerebrovascular diseases (Pan et al. 2011), and obesity (Milaneschi et al. 2019).”
Bidirectional causal relationship between depression and Type 2 diabetes: a multi-ancestry and sex stratified Mendelian Randomization analysis
Liu, H.-Y., Xiang, J., Xie, Q., & Xiang, H. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.119879 · Cited by 4
Psychological and behavioral effects of GLP-1 and GIP agonists in weight loss: a comprehensive review
Ameer, F., Villacres, N. Y., Bustos, D., Shah, P., Appah, N., Luzaya, G. N., Corradi, F., Bakare, I. S., Trujillo, J. V., Mylavarapu, M., et al. (2025) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-025-01770-x · Cited by 5
Immunometabolic blood biomarkers of developmental trajectories of depressive symptoms: findings from the ALSPAC birth cohort
Tsang, R. S. M., Stow, D., Kwong, A. S. F., Donnelly, N. A., Fraser, H., Barroso, I., Holmans, P., Owen, M. J., Wood, M. L., Kirov, G., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03311-7 · Cited by 12
“You will receive a response within 10 working days to advise you whether your proposal has been approved.”
Depression: epigenetics and epitranscriptomic modifications
Banerjee, S., Shrilaxmi, M. S., Banerjee, S., Prajwal, B. G., Smith, C., D’Mello, S. R., & Dastidar, S. G. (2025) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2025.2602171 · Cited by 4
Association between green space exposure and elderly health: a systematic review and meta-analysis
Wang, M., Che, Y., Tan, X., Zhang, N., Yu, S., & Yan, P. (2026) · BMC Public Health · doi:10.1186/s12889-025-26137-y · Cited by 7
“Furthermore, higher air pollut-ant levels are strongly associated with increased risks of depression and anxiety [67–69].”
Beyond weight loss: multisystem benefits of obesity medications
Savas, M., Kuckuck, S., Boon, M. R., & van Rossum, E. F. C. (2026) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(26)00100-2 · Cited by 4
Self-citation
Obesity and Cardiovascular Disease: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2026
Bays, H. E., Varney, C., Alexander, L., Ng, J., Tondt, J., Weber, C., Christensen, S. M., Burridge, K., Brown, C., Bindlish, S., et al. (2026) · Obesity Pillars · doi:10.1016/j.obpill.2026.100283 · Cited by 4
Leptin’s Inverse Association With Brain Morphology and Depressive Symptoms: A Discovery and Confirmatory Study Across 2 Independent Samples
Zhang, Y., Munshi, S., Burrows, K., Kuplicki, R., Figueroa‐Hall, L. K., Aupperle, R. L., Khalsa, S. S., Teague, T. K., Taki, Y., Paulus, M. P., et al. (2024) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2024.04.005 · Cited by 4
Assessing the role of antioxidant and pro-oxidant balance in mediating the relationship between vitamin K intake and depressive symptoms in adults
Wang, L., Huang, S., Feng, Z.-Y., Xiao, J., Luo, G., & Zhang, Y. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1384489 · Cited by 4
“The relationship between obesity and depression is bidirectionalthe presence of one increases the risk for developing the other (50).”
Background
Contribution of obesity in the association between fast-food consumption and depression: A mediation analysis
Shafiee, A., Aghajanian, S., Heidari, E., Abbasi, M., Jafarabady, K., Baradaran, S., & Bakhtiyari, M. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.07.036 · Cited by 7
Structural connectivity of thalamic subnuclei in major depressive disorder: An ultra-high resolution diffusion MRI study at 7-Tesla
Liu, W., Heij, J., Liu, S., Liebrand, L. C., Caan, M. W. A., van der Zwaag, W., Veltman, D. J., Lü, L., Aghajani, M., & van Wingen, G. A. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.11.009 · Cited by 5
The impact of depression on risk of malignant glioma: A nationwide cohort study
Eun, J., Um, Y. H., Han, K., Joo, W., & Yang, S. (2024) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2024.111982 · Cited by 4
“However, according to the re-sults of this cohort, the effect of BMI is not significant when analyzed specifically for patients diagnosed with glioma[20,21].”
Increased risk of type 2 diabetes after traumatic amputation: a nationwide retrospective cohort study
Yoo, J. E., Lee, D., Kim, B., et al. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1437860 · Cited by 4
Bibliometric insights into astrocytic roles in depression and treatment
Lin, L., Guo, Z., Ren, Z., Feng, Y., Fang, P., Wang, T., & Chen, M. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1521398 · Cited by 6
Association between adolescent obesity and early adulthood healthcare utilization—a two-cohort prospective study
Hagman, E., Halsteinli, V., Putri, R. R., Edwards, C. H., Bjørnelv, G. W., Marcus, C., & Ødegård, R. A. (2025) · BMC Medicine · doi:10.1186/s12916-025-03866-w · Cited by 5
BMI trajectories, changes and their potential associations with the risk of depression during adulthood: A cross-sectional study from NHANES 2005–2018
Yang, B., Geng, H., Chen, J., Yin, H., Gu, J., Xu, Z., & Meng, X. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.119436 · Cited by 4
Food Addiction Is Strongly Associated With Psychopathology and Reduced Psychological Well‐Being Among Adults Irrespective of BMI
Horsager, C., Færk, E., Bruun, J. M., Lauritsen, M. B., & Østergaard, S. D. (2025) · European Eating Disorders Review · doi:10.1002/erv.70011 · Cited by 4
“Furthermore, it is well‐established that high BMI is linked to depression (Luppino et al. 2010; Mannan et al. 2016; Milaneschi et al. 2019) and that this link is likely causal (Speed et al. 2019).”
The Association between Ultra‐Processed Foods and Depression, Anxiety and Sleep in Adults: A Cross‐Sectional Study in Iran
Abdollahpour, N., Fard, S. A. M., Salahmanesh, A., Hatamzadeh, H., Moeini, R., Soflaei, S. S., Seifi, N., & Ghayour‐Mobarhan, M. (2025) · Food Science & Nutrition · doi:10.1002/fsn3.70316 · Cited by 9
“UPFs are associated with chronic nutrition-related diseases such as obesity and metabolic syndrome, both of which are bidirectionally linked to depression (Milaneschi et al. 2019).”
Obesity, chronic kidney disease progression and the role of the adipokine C1q/TNF related protein-3
Barbieri, D., Goicoechea, M., Verde, E., et al. (2022) · Nefrología · doi:10.1016/j.nefro.2022.02.002 · Cited by 4
Collateralizing ventral subiculum melanocortin 4 receptor circuits regulate energy balance and food motivation
Singh, U., Saito, K., Khan, M. Z., Jiang, J., Toth, B. A., Rodeghiero, S. R., Dickey, J. E., Deng, Y., Deng, G., Kim, Y.-C., et al. (2023) · Physiology & Behavior · doi:10.1016/j.physbeh.2023.114105 · Cited by 7
“Hippocampal dysfunction has been implicated in the pathogenesis of major depressive disorder (MDD) [1; 2], a serious mental illness characterized by not only depressed mood and anhedonia but also appetite disturbance and dysregulated body weight homeostasis [3-7].”
Brain deficit patterns of metabolic illnesses overlap with those for major depressive disorder: A new metric of brain metabolic disease
Hatch, K. S., Gao, S., Ma, Y., Russo, A., Jahanshad, N., Thompson, P. M., Adhikari, B. M., Bruce, H. A., van der Vaart, A. D., Sotiras, A., et al. (2023) · Human Brain Mapping · doi:10.1002/hbm.26235 · Cited by 5
“This is consistent with findings that MET co-occur with MDD at nearly five times versus normal controls and double the rates versus other mental illnesses (Jantaratnotai et al., 2017; Luo et al., 2018; Malmir et al., 2019; Milaneschi et al., 2019).”
Result
Multimorbidity patterns: obesity as the main modifiable risk factor in adult women in Southern Brazil
Franken, D. L., da Costa, J. S. D., Olinto, M. T. A., Stürmer, J., Bordin, R. B., & Paniz, V. M. V. (2023) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000642 · Cited by 4
“…mental health diseases, evidence has shown an association between obesity and psychiatric disorders, such as anxiety and, mainly, depression (44,45), treating it as a bidirectional relationship, intertwined by a series of biological, psychological, and even behavioral mechanisms, which result…”
Background
Causal Effect of Relative Carbohydrate Intake on Hypertension through Psychological Well-Being and Adiposity: A Mendelian Randomization Study
Ye, C., Kong, L., Wang, Y., Dou, C., Xu, M., Zheng, J., Zheng, R., Xu, Y., Li, M., Zhao, Z., et al. (2023) · Nutrients · doi:10.3390/nu15224817 · Cited by 4
“Our ﬁndings provide novel evidence for causal risk factors and pathological pathways of hypertension and encourage an integrated and precise approach to promote dietary behavior, psychological well-being, and weight control to tackle the rapid epidemic and heavy burden of hypertension.”
Background
The Influence of Adiposity Levels on the Relation between Perfluoroalkyl Substances and High Depressive Symptom Scores in Czech Adults
Neto, G. D. A. M., Bobák, M., Gonzalez-Rivas, J. P., & Klánová, J. (2023) · Toxics · doi:10.3390/toxics11110946 · Cited by 4
“…a plausible inﬂuence on adipose tissue mass [22,23], and the established interplay between depression and obesity, notably through the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis [24,25], our inquiry extends to elucidate potential connections with a focus on body fat status.”
Background
Dietary Factors and the Risk of Depression among Women with Polycystic Ovary Syndrome
Łagowska, K., Bajerska, J., & Pieczyńska-Zając, J. M. (2024) · Nutrients · doi:10.3390/nu16060763 · Cited by 6
“A vicious circle is thus observed because the existence of one elevates the likelihood of developing the other [13].”
Background
Polypharmacy in psychiatry and weight gain: longitudinal study of 832 patients hospitalized for depression or schizophrenia, along with data of 3180 students from Europe, the U.S., South America, and China
Stassen, H. H., Bachmann, S., Bridler, R., Cattapan, K., & Seifritz, E. (2024) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-024-01767-2 · Cited by 4
Which Factors Are Associated with Persistence of Depressive and Anxiety Symptoms in Patients Affected by Atopic Dermatitis despite 2-Year Treatment with Dupilumab?
Ferrucci, S. M., Tavecchio, S., Ceresa, A., et al. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13071980 · Cited by 4
“…of depression in our sample, several studies indicate that a higher BMI is associated with more severe mood disorders [41,42] as a result of common pathophysiological processes underlying obesity and depressive illness (e.g., leptin/insulin dysregulation or intestinal microbiome alterations) [43].”
Result
Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach
Pérez-Gutiérrez, A. M., Carmona, R., Loucera, C., Cervilla, J. A., Gutiérrez, B., Molina, E., López-López, D., Pérez-Florido, J., Zarza-Rebollo, J. A., López‐Isac, E., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02609-2 · Cited by 5
Dose-response association of obesity and risk of mental health among tehranian residents: result of a cross-sectional study
Jibril, A. T., Ganjeh, B. J., Mirrafiei, A., Firouzi, M., Norouziasl, R., Ghaemi, S., Bafkar, N., Jayedi, A., Djafarian, K., & Shab‐Bidar, S. (2024) · BMC Public Health · doi:10.1186/s12889-024-18670-z · Cited by 5
“The red dash lines indicates the knots, the black dash lines represents the lower and upper confidence intervals, the solid black line shows the estimate [67, 68].”
Background
Analysis of correlation between BMI and TWL% outcome following metabolic and bariatric surgery: a retrospective study using restricted cubic spline
Chen, G., Li, Z., Wang, L., Wuyun, Q., Sang, Q., Wang, J., Wang, Z., Tian, C., Yu, C., Amin, B., et al. (2024) · BMC Surgery · doi:10.1186/s12893-024-02455-7 · Cited by 4
Clinical Factors and Biomarkers Associated with Depressive Disorders in Older Patients Affected by Chronic Kidney Disease (CKD): Does the Advanced Glycation End Products (AGEs)/RAGE (Receptor for AGEs) System Play Any Role?
Buoli, M., Dozio, E., Caldiroli, L., Armelloni, S., Vianello, E., Romanelli, M. M. C., Castellano, G., & Vettoretti, S. (2024) · Geriatrics · doi:10.3390/geriatrics9040099 · Cited by 4
“…disorder (MDD), represent prevalent and disabling conditions that are often concomitant with a number of medical conditions, such as autoimmune diseases (e.g., rheumatoid arthritis and atopic dermatitis) [1,2], cardio-vascular conditions [3], overweight [4,5], and chronic kidney disease (CKD) [6].”
Background
Modifiable risk factors and excess mortality in depression: Data from the UK Biobank
Barros, V. B., & Filho, A. D. P. C. (2024) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2024.08.010 · Cited by 5
Puerarin Ameliorates Ferroptosis in Neuronal Injury Through the PI3K/AKT Signaling Pathway
Hu, R., Peng, Z.-T., & Liu, H. (2024) · Nutrition and Cancer · doi:10.1080/01635581.2024.2422637 · Cited by 4
“Previous studies have reported that high-dose corticosterone can lead to abnormal behavioral and neurochemical changes, reduce hippocampal volumes, and decrease hippocampal cells in patients with MDD.”
Influential
The Relationship Between BRI and Depressive Symptoms in Chinese Older Adults: A CLHLS‐Based Study
Wang, Y., Yang, Y., Wang, W., Chen, Q. Y., Jia, W., & Li, L. (2024) · International Journal of Methods in Psychiatric Research · doi:10.1002/mpr.70009 · Cited by 5
Combined association of physical activity and depressive symptoms with cardiometabolic risk factors in Chilean adults
Hernández, P. A. F., Farías‐Valenzuela, C., Rezende, L. F. M., Nascimento, M. D. M., Marques, A., de Victo, E. R., & Ferrari, G. (2024) · Scientific Reports · doi:10.1038/s41598-024-82396-6 · Cited by 6
The curvilinear relationship between hepatic steatosis index and depression: Findings from the NHANES
Jiang, C., Wang, W., Wang, J., et al. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.01.083 · Cited by 4

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
ORCID: Milaneschi, Yuri
Simmons, W. Kyle
Penninx, Brenda WJH
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2018-02-16
Volume: 24
Issue: 1
Pages: 18-33
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/s41380-018-0017-5
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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Depression and obesity: evidence of shared biological mechanisms

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