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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Factors Associated with the Development of Depression and the Influence of Obesity on Depressive Disorders: A Narrative Review
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“A study conducted in Korea that evaluated middle-aged individuals (40 to 60 years old) found that poor dietary quality, inadequate protein intake, and irregular meals were associated with an increased risk of depression [120].”
Background
Interaction mechanisms between major depressive disorder and non-alcoholic fatty liver disease
Shao, Q., Wu, Y., Ji, J., Xu, T., Yu, Q., Ma, C., Liao, X., Cheng, F., & Wang, X. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.711835 · Cited by 32
“Nevertheless, the pathogeneses for these diseases have not been fully established because these proximal mechanisms may be seriously affected by more distal behavioral and psychosocial factors (193).”
Background
Interventions targeting comorbid depression and overweight/obesity: A systematic review
Cao, B., Xu, J., Li, R., Teopiz, K. M., McIntyre, R. S., & Chen, H. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.07.027 · Cited by 32
The Way to a Human’s Brain Goes Through Their Stomach: Dietary Factors in Major Depressive Disorder
Aly, J. S., & Engmann, O. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.582853 · Cited by 36
Mendelian randomisation study of body composition and depression in people of East Asian ancestry highlights potential setting-specific causality
O’Loughlin, J., Casanova, F., Fairhurst-Hunter, Z., Hughes, A., Bowden, J., Watkins, E. R., Freathy, R. M., Millwood, I. Y., Lin, K., Chen, Z., et al. (2023) · BMC Medicine · doi:10.1186/s12916-023-02735-8 · Cited by 33
“Finally, we removed a variant in the MC4R gene (rs2229616) due to the potential strong influence of this SNP on both obesity and depression [30].”
Method
Brain–body communication in metabolic control
Furlan, A., & Petrus, P. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.08.014 · Cited by 34
Food addiction comorbid to mental disorders: A nationwide survey and register‐based study
Horsager, C., Færk, E., Lauritsen, M. B., & Østergaard, S. D. (2021) · International Journal of Eating Disorders · doi:10.1002/eat.23472 · Cited by 37
Canonical Chinese medicine formula Danzhi-Xiaoyao-San for treating depression: A systematic review and meta-analysis
Wang, X., Feng, S., Wang, Y., Zhang, N., Wang, Z., & Zhang, Y. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114960 · Cited by 34
How gut hormones shape reward: A systematic review of the role of ghrelin and GLP-1 in human fMRI
Schulz, C., Vezzani, C., & Kroemer, N. B. (2023) · Physiology & Behavior · doi:10.1016/j.physbeh.2023.114111 · Cited by 33
An inflamed subtype of difficult-to-treat depression
Suneson, K., Grudet, C., Ventorp, F., Malm, J., Asp, M., Westrin, Å., & Lindqvist, D. (2023) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110763 · Cited by 32
Metabolically healthy status and BMI in relation to depression: A systematic review of observational studies
Malmir, H., Mirzababaei, A., Moradi, S., Rezaei, S., Mirzaei, K., & Dadfarma, A. (2019) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2019.01.027 · Cited by 31
Socioeconomic inequalities in co-morbidity of overweight, obesity and mental ill-health from adolescence to mid-adulthood in two national birth cohort studies
Khanolkar, A. R., & Patalay, P. (2021) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2021.100106 · Cited by 31
“Exposure to early life stress and chronic stress over time can lead to hyperactivation of the HPA-axis resulting in high levels of cortisol associated with increased risk for both depression and obesity [48].”
Background
Microbiome and immuno-metabolic dysregulation in patients with major depressive disorder with atypical clinical presentation
Refisch, A., Şen, Z. D., Klassert, T. E., Busch, A., Besteher, B., Danyeli, L. V., Helbing, D. L., Schulze‐Späte, U., Stallmach, A., Bauer, M. W., et al. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109568 · Cited by 33
Strength training has antidepressant effects in people with depression or depressive symptoms but no other severe diseases: A systematic review with meta-analysis
Rossi, F. E., dos Santos, G. G., Rossi, P. A. Q., Stubbs, B., Schuch, F. B., & Neves, L. M. (2024) · Psychiatry Research · doi:10.1016/j.psychres.2024.115805 · Cited by 41
Risk factors, prevention and treatment of weight gain associated with the use of antidepressants and antipsychotics: a state-of-the-art clinical review
Solmi, M., Miola, A., Capone, F., Pallottino, S., Højlund, M., Firth, J., Siskind, D. J., Holt, R. I. G., Corbeil, O., Cortese, S., et al. (2024) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2024.2396396 · Cited by 35
Translational evaluation of metabolic risk factors impacting DBS efficacy for PD-related sleep and depressive disorders: preclinical, prospective and cohort studies
Yao, L., Chen, R., Zheng, Z., Hatami, M., Koç, S., Wang, X., Bai, Y., Yao, C., Lu, G., & Skutella, T. (2024) · International Journal of Surgery · doi:10.1097/js9.0000000000002081 · Cited by 31
“Speci ﬁ cally, being overweight is linked to a heightened risk of experiencing depression, and conversely, depression can lead to increased likelihood of gaining weight [29] .”
Risk of Suicide, Hair Loss, and Aspiration with GLP1-Receptor Agonists and Other Diabetic Agents: A Real-World Pharmacovigilance Study
Nakhla, M., Nair, A. V., Balani, P., Ujjawal, A., Kumar, P. A., Dasari, M., Yukselen, Z., Bansal, K., Ganatra, S., & Dani, S. S. (2024) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-024-07613-w · Cited by 32
“Depression and obesity are two commonly co-existing comorbidities that put patients at an increased risk for suicidal ideation [25].”
Relationship between body mass index and neuropsychiatric symptoms: Evidence and inflammatory correlates
Huet, L., Delgado, I., Dexpert, S., Sauvant, J., Aouizerate, B., Beau, C., Forestier, D., Ledaguenel, P., Magne, E., & Capuron, L. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.02.031 · Cited by 33
Prevalence of depression and associated factors among patients with type 2 diabetes mellitus in eastern Sudan
Omar, S. M., Musa, I. R., Idrees, M. B., & Adam, I. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03357-1 · Cited by 35
Pathophysiology of Major Depression by Clinical Stages
de Menezes Galvão, A. C., Almeida, R. N., de Sousa, G. M., Leocadio-Miguel, M. A., Palhano-Fontes, F., de Araujo, D. B., Lobão-Soares, B., Maia-de-Oliveira, J. P., Nunes, E. A., Hallak, J. E. C., et al. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.641779 · Cited by 31
Association between visceral adipose tissue and major depressive disorder across the lifespan: A scoping review
Lee, J., Busler, J. N., Millett, C. E., Principe, J. L., Levin, L., Corrigan, A., & Burdick, K. E. (2021) · Bipolar Disorders · doi:10.1111/bdi.13130 · Cited by 29
Association between Dietary Fiber Intake and Incidence of Depression and Anxiety in Patients with Essential Hypertension
Liu, Y., Ju, Y., Cui, L., Liu, T., Hou, Y., Wu, Q., Ojo, O., Du, X., & Wang, X. (2021) · Nutrients · doi:10.3390/nu13114159 · Cited by 31
“that energy intake is associated with the prevalence of depression [40,41].”
Background
Predicting depressive symptoms in middle-aged and elderly adults using sleep data and clinical health markers: A machine learning approach
Gomes, S. R. B. S., von Schantz, M., & Leocádio-Miguel, M. A. (2023) · Sleep Medicine · doi:10.1016/j.sleep.2023.01.002 · Cited by 34
The connection of 5-alpha reductase inhibitors to the development of depression
Saengmearnuparp, T., Lojanapiwat, B., Chattipakorn, N., & Chattipakorn, S. C. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112100 · Cited by 28
Epidrugs in the Therapy of Central Nervous System Disorders: A Way to Drive on?
Gladkova, M. G., Leidmaa, E., & Anderzhanova, E. A. (2023) · Cells · doi:10.3390/cells12111464 · Cited by 31
“Moreover, psychiatric disorders and obesity are shown to co-occur [214].”
Background
Negative association between Body Roundness Index and bone mineral density: insights from NHANES
Ding, Z., Zhuang, Z., Tang, R., Qu, X., Huang, Z., Maji, S., & Feng, Y. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1448938 · Cited by 30
Lipid metabolic dysregulation-induced neuroinflammation in the pathophysiology of major depressive disorder
Ge, Z., Hu, Y., Kan, W., Li, L., Xu, J., Zhang, Y., Zheng, N., Wang, G., & Du, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1625087 · Cited by 35
“These genes were highly expressed in key brain regions regulating appetite and energy homeostasis (e.g., hypothalamus and pituitary gland), as well as mood-regulating brain regions (e.g., hippocampus and limbic system) (32).”
Depression-Associated Gene Negr1-Fgfr2 Pathway Is Altered by Antidepressant Treatment
Carboni, L., Pischedda, F., Piccoli, G., Lauria, M., Musazzi, L., Popoli, M., Mathé, A. A., & Domenici, E. (2020) · Cells · doi:10.3390/cells9081818 · Cited by 29
“The aim of this study was to investigate if the Negr1-Fgfr2 pathway was modulated by antidepressant treatment, since this gene has been genetically associated to both MDD and obesity, two co-occurring conditions believed to share common neurobiological alterations [52].”
Background
Depression and obesity among females, are sex specificities considered?
Baldini, I., Casagrande, B. P., & Estadella, D. (2021) · Archives of Women s Mental Health · doi:10.1007/s00737-021-01123-6 · Cited by 33
Comorbid depression and obesity among adults in Germany: Effects of age, sex, and socioeconomic status
Chae, W. R., Schienkiewitz, A., Du, Y., Hapke, U., Otte, C., & Michalski, N. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.12.025 · Cited by 29
Comorbid depression and obesity, and its transition on the risk of functional disability among middle-aged and older Chinese: a cohort study
Lin, L., Bai, S., Qin, K., Wong, C. K. H., Wu, T., Chen, D., Lu, C., Chen, W., & Guo, V. Y. (2022) · BMC Geriatrics · doi:10.1186/s12877-022-02972-1 · Cited by 29
“Additionally, these two conditions often occur simultaneously with a bidirectional association due to shared genetic, metabolic, and psychosocial pathways [9, 10].”
Background
Ghrelin as a Biomarker of “Immunometabolic Depression” and Its Connection with Dysbiosis
Gajewska, A., Strzelecki, D., & Gawlik-Kotelnicka, O. (2023) · Nutrients · doi:10.3390/nu15183960 · Cited by 33
“Depressed individuals also have an elevated risk of obesity [50,51] and insulin resistance [52,53].”
Background
The relationship between BMI and depression: a cross-sectional study
Cui, H., Xiong, Y., Wang, C., Ye, J., & Zhao, W. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1410782 · Cited by 28
Depression, treatable cardiovascular risk factors and incident cardiac events in the Gazel cohort
Hamieh, N. M., Meneton, P., Wiernik, E., Limosin, F., Zins, M., Goldberg, M., Melchior, M., & Lemogne, C. (2018) · International Journal of Cardiology · doi:10.1016/j.ijcard.2018.10.013 · Cited by 29
“analysis did not search for an interaction with overweight or obesity, despite their strong association with depression [47, 48].”
Background
Anxiety-like behavior in female mice is modulated by STAT3 signaling in midbrain dopamine neurons
Fernandes, M. F., Lau, D., Sharma, S., & Fulton, S. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.04.013 · Cited by 28
Lipid endocannabinoids in energy metabolism, stress and developmental programming
de Almeida, M. M., Dias-Rocha, C. P., Calviño, C., & Trevenzoli, I. H. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111522 · Cited by 27
Causality of abdominal obesity on cognition: a trans-ethnic Mendelian randomization study
Wang, S., Su, M., Chen, C., Lin, K., Feng, Y. A., Hsiao, P., Pan, Y., & Wu, C. (2022) · International Journal of Obesity · doi:10.1038/s41366-022-01138-8 · Cited by 28
“INTRODUCTION Obesity is an important public health issue owing to its increasing prevalence [1] and adverse health effects on cardiovascular disease, diabetes, cancer, and depression [2, 3].”
Background
Correlation analysis between per-fluoroalkyl and poly-fluoroalkyl substances exposure and depressive symptoms in adults: NHANES 2005–2018
Sun, X., Yang, X., Zhang, Y., Liu, Y., Xiao, F., Guo, H., & Liu, X. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.167639 · Cited by 30
Sex-dependence and comorbidities of the early-life adversity induced mental and metabolic disease risks: Where are we at?
Reemst, K., Ruigrok, S. R., Bleker, L. S., Naninck, E. F. G., Ernst, T. R., Kotah, J. M., Lucassen, P. J., Roseboom, T. J., Pollux, B. J. A., de Rooij, S. R., et al. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104627 · Cited by 26
Weight changes in adults with major depressive disorder: A systematic review and meta-analysis of prospective studies
Treviño‐Alvarez, A. M., Sánchez-Ruiz, J. A., Barrera, F. J., Rodríguez-Bautista, M., Romo‐Nava, F., McElroy, S. L., & Barboza, A. B. C. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.03.050 · Cited by 28
Effects of vitamin D and/or magnesium supplementation on mood, serum levels of BDNF, inflammatory biomarkers, and SIRT1 in obese women: a study protocol for a double-blind, randomized, placebo-controlled trial
Abiri, B., & Vafa, M. (2020) · Trials · doi:10.1186/s13063-020-4122-9 · Cited by 27
Association between glucagon‐like peptide ‐1 receptor agonists and risk of suicidality: A comprehensive analysis of the global pharmacovigilance database
Kim, T. H., Lee, K., Park, S., Cho, H., Park, J., Jo, H., Son, Y., Kim, S., Kang, J., Smith, L., et al. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15864 · Cited by 26
Serum and plasma levels of brain-derived neurotrophic factor in individuals with eating disorders (EDs): a systematic review and meta-analysis
Shobeiri, P., Bagherieh, S., Mirzayi, P., Kalantari, A., Mirmosayyeb, O., Teixeira, A. L., & Rezaei, N. (2022) · Journal of Eating Disorders · doi:10.1186/s40337-022-00630-w · Cited by 28
“Furthermore, it has been shown that antidepressant agents up-regulate the expression of the BDNF gene [55, 57].”
Background

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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