{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:25:46Z","timestamp":1790475946258,"version":"4.1.0"},"reference-count":37,"publisher":"IMR Press","issue":"3","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science foundation of Hunan Province","award":["2025JJ81092"],"award-info":[{"award-number":["2025JJ81092"]}]},{"name":"Clinical Medical Technology Innovation Guide Project of Hunan Province","award":["2021SK51901"],"award-info":[{"award-number":["2021SK51901"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background: A high-fat diet (HFD) has been implicated in the induction of depressive-like behaviors, yet the underlying mechanisms remain incompletely elucidated. Growing evidence indicates that microglia-mediated neuroinflammation plays a critical role in the pathogenesis of depression, with excessive lipid droplet (LD) accumulation emerging as an early trigger for neuroinflammatory cascades. The aim of this study was to investigate microglial LD accumulation and the associated neuroinflammatory response in a model of HFD-induced depression. Methods: Diet-induced obese (DIO) mice were compared with normal control (Con) mice. Depressive-like behaviors were evaluated through a battery of behavioral tests. Hippocampal neuronal damage and microglial activation were assessed using histological and immunofluorescence techniques. A co-culture system of glial cell-enriched isolates and hippocampal neurons was employed to evaluate the neurotoxic potential of DIO microglia. LD accumulation in microglia was quantified in vivo and in vitro using Bodipy staining, Oil Red O staining, and electron microscopy. Untargeted lipidomics was performed on glial cells to characterize alterations in lipid metabolism. Results: Compared with Con mice, DIO mice exhibited significant depressive-like behaviors and hippocampal neuronal damage, accompanied by enhanced microglia-mediated neuroinflammation. In the co-culture system, microglia from DIO mice demonstrated increased neurotoxicity toward hippocampal neurons. Bodipy staining and electron microscopy revealed increased accumulation of LDs in the hippocampal microglia of DIO mice. This was further confirmed in glial cells in vitro. Lipidomic profiling identified substantial disturbances in lipid metabolism in DIO microglia. Conclusion: Diet-induced obesity leads to depressive-like behaviors and hippocampal neuronal damage, which is associated with microglia-mediated neuroinflammation and intracellular accumulation of LDs. The enhanced neurotoxicity of DIO microglia, coupled with pronounced lipid metabolic dysregulation, suggests that lipid-laden microglia may contribute to the link between obesity and depression via neuroinflammatory mechanisms.<\/jats:p>","DOI":"10.31083\/jin47039","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T09:35:19Z","timestamp":1774949719000},"source":"Crossref","is-referenced-by-count":1,"title":["Microglial Lipid Droplet Accumulation: A Pathological Nexus Between Obesity and Depression"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3168-8846","authenticated-orcid":true,"given":"Xijin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7583-9001","authenticated-orcid":true,"given":"Jiacheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2248-9719","authenticated-orcid":true,"given":"Yangzhi","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7417-2979","authenticated-orcid":true,"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6281-0169","authenticated-orcid":true,"given":"Zhengyang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4167-9703","authenticated-orcid":true,"given":"Yili","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4154-6005","authenticated-orcid":true,"given":"Zhao","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Simon GE, Moise N, Mohr DC. Management of Depression in Adults: A Review. JAMA. 2024; 332: 141\u2013152.","DOI":"10.1001\/jama.2024.5756"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Lof J, Smits K, Melotte V, Kuil LE. The health effect of probiotics on high-fat diet-induced cognitive impairment, depression and anxiety: A cross-species systematic review. Neuroscience and Biobehavioral Reviews. 2022; 136: 104634.","DOI":"10.1016\/j.neubiorev.2022.104634"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Guillemot-Legris O, Muccioli GG. Obesity-Induced Neuroinflammation: Beyond the Hypothalamus. Trends in Neurosciences. 2017; 40: 237\u2013253.","DOI":"10.1016\/j.tins.2017.02.005"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Kocamer \u015eahin \u015e, Aslan E. Inflammation as a Neurobiological Mechanism of Cognitive Impairment in Psychological Stress. Journal of Integrative Neuroscience. 2024; 23: 101.","DOI":"10.31083\/j.jin2305101"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Wang XL, Li L. Microglia Regulate Neuronal Circuits in Homeostatic and High-Fat Diet-Induced Inflammatory Conditions. Frontiers in Cellular Neuroscience. 2021; 15: 722028.","DOI":"10.3389\/fncel.2021.722028"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nature Neuroscience. 2020; 23: 194\u2013208.","DOI":"10.1038\/s41593-019-0566-1"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Wei W, Lattau SSJ, Xin W, Pan Y, Tatenhorst L, Zhang L, et al. Dynamic Brain Lipid Profiles Modulate Microglial Lipid Droplet Accumulation and Inflammation Under Ischemic Conditions in Mice. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2024; 11: e2306863.","DOI":"10.1002\/advs.202306863"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Zareba J, Cattaneo EF, Villani A, Othman A, Streb S, Peri F. NPC1 links cholesterol trafficking to microglial morphology via the gastrosome. Nature Communications. 2024; 15: 8638.","DOI":"10.1038\/s41467-024-52874-6"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Zhang Y, Du B, Zou M, Peng B, Rao Y. Neuronal Ceroid Lipofuscinosis-Concepts, Classification, and Avenues for Therapy. CNS Neuroscience & Therapeutics. 2025; 31: e70261.","DOI":"10.1111\/cns.70261"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Evans AK, Saw NL, Woods CE, Vidano LM, Blumenfeld SE, Lam RK, et al. Impact of high-fat diet on cognitive behavior and central and systemic inflammation with aging and sex differences in mice. 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Biomaterials. 2023; 293: 121850.","DOI":"10.1016\/j.biomaterials.2022.121850"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. European Journal of Pharmacology. 2003; 463: 3\u201333.","DOI":"10.1016\/s0014-2999(03)01272-x"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Madison CA, Kuempel J, Albrecht GL, Hillbrick L, Jayaraman A, Safe S, et al. 3,3\u2019-Diindolylmethane and 1,4-dihydroxy-2-naphthoic acid prevent chronic mild stress induced depressive-like behaviors in female mice. Journal of Affective Disorders. 2022; 309: 201\u2013210.","DOI":"10.1016\/j.jad.2022.04.106"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Carloni S, Rescigno M. The gut-brain vascular axis in neuroinflammation. Seminars in Immunology. 2023; 69: 101802.","DOI":"10.1016\/j.smim.2023.101802"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Jadiya P, Garbincius JF, Elrod JW. Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling. Acta Neuropathologica Communications. 2021; 9: 124.","DOI":"10.1186\/s40478-021-01224-4"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Haney MS, P\u00e1lovics R, Munson CN, Long C, Johansson PK, Yip O, et al. APOE4\/4 is linked to damaging lipid droplets in Alzheimer\u2019s disease microglia. Nature. 2024; 628: 154\u2013161.","DOI":"10.1038\/s41586-024-07185-7"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Gouna G, Klose C, Bosch-Queralt M, Liu L, Gokce O, Schifferer M, et al. TREM2-dependent lipid droplet biogenesis in phagocytes is required for remyelination. The Journal of Experimental Medicine. 2021; 218: e20210227.","DOI":"10.1084\/jem.20210227"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Wang A, Wan X, Zhuang P, Jia W, Ao Y, Liu X, et al. High fried food consumption impacts anxiety and depression due to lipid metabolism disturbance and neuroinflammation. Proceedings of the National Academy of Sciences of the United States of America. 2023; 120: e2221097120.","DOI":"10.1073\/pnas.2221097120"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Cashikar AG, Toral-Rios D, Timm D, Romero J, Strickland M, Long JM, et al. Regulation of astrocyte lipid metabolism and ApoE secretionby the microglial oxysterol, 25-hydroxycholesterol. Journal of Lipid Research. 2023; 64: 100350.","DOI":"10.1016\/j.jlr.2023.100350"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"de Los Angeles Gomez M, Serrai H, Bhaduri S, Laleg-Kirati TM. A novel method for Magnetic Resonance Spectroscopy lipid signal suppression using Semi-classical signal analysis and Bidirectional Long short-term memory. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference. 2022; 2022: 317\u2013320.","DOI":"10.1109\/EMBC48229.2022.9871645"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Kim SW, Wiers CE, Tyler R, Shokri-Kojori E, Jang YJ, Zehra A, et al. Influence of alcoholism and cholesterol on TSPO binding in brain: PET [11C] PBR28 studies in humans and rodents. Neuropsychopharmacology. 2018; 43: 1832\u20131839.","DOI":"10.1038\/s41386-018-0085-x"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Beyazy\u00fcz M, Albayrak Y, E\u011filmez OB, Albayrak N, Beyazy\u00fcz E. Relationship between SSRIs and Metabolic Syndrome Abnormalities in Patients with Generalized Anxiety Disorder: A Prospective Study. Psychiatry Investigation. 2013; 10: 148\u2013154.","DOI":"10.4306\/pi.2013.10.2.148"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Xu DH, Du JK, Liu SY, Zhang H, Yang L, Zhu XY, et al. Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1. Cell Death & Disease. 2023; 14: 278.","DOI":"10.1038\/s41419-023-05800-5"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Dang R, Wang M, Li X, Wang H, Liu L, Wu Q, et al. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1\/Nrf2\/HO-1\/Gpx4 pathway. Journal of Neuroinflammation. 2022; 19: 41.","DOI":"10.1186\/s12974-022-02400-6"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Fang M, Yu Q, Ou J, Lou J, Zhu J, Lin Z. The Neuroprotective Mechanisms of PPAR-\u03b3: Inhibition of Microglia-Mediated Neuroinflammation and Oxidative Stress in a Neonatal Mouse Model of Hypoxic-Ischemic White Matter Injury. CNS Neuroscience & Therapeutics. 2024; 30: e70081.","DOI":"10.1111\/cns.70081"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Yeh JH, Wang KC, Kaizaki A, Lee JW, Wei HC, Tucci MA, et al. Pioglitazone Ameliorates Lipopolysaccharide-Induced Behavioral Impairment, Brain Inflammation, White Matter Injury and Mitochondrial Dysfunction in Neonatal Rats. International Journal of Molecular Sciences. 2021; 22: 6306.","DOI":"10.3390\/ijms22126306"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Leal AF, Suarez DA, Echeverri-Pe\u00f1a OY, Albarrac\u00edn SL, Alm\u00e9ciga-D\u00edaz CJ, Espejo-Mojica \u00c1J. Sphingolipids and their role in health and disease in the central nervous system. Advances in Biological Regulation. 2022; 85: 100900.","DOI":"10.1016\/j.jbior.2022.100900"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Phung NV, Rong F, Xia WY, Fan Y, Li XY, Wang SA, et al. Nervonic acid and its sphingolipids: Biological functions and potential food applications. Critical Reviews in Food Science and Nutrition. 2024; 64: 8766\u20138785.","DOI":"10.1080\/10408398.2023.2203753"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Zieli\u0144ska M, \u0141uszczki E, Micho\u0144ska I, Dere\u0144 K. The Mediterranean Diet and the Western Diet in Adolescent Depression-Current Reports. Nutrients. 2022; 14: 4390.","DOI":"10.3390\/nu14204390"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Li Y, Lv MR, Wei YJ, Sun L, Zhang JX, Zhang HG, et al. Dietary patterns and depression risk: A meta-analysis. Psychiatry Research. 2017; 253: 373\u2013382.","DOI":"10.1016\/j.psychres.2017.04.020"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Firth J, Marx W, Dash S, Carney R, Teasdale SB, Solmi M, et al. The Effects of Dietary Improvement on Symptoms of Depression and Anxiety: A Meta-Analysis of Randomized Controlled Trials. Psychosomatic Medicine. 2019; 81: 265\u2013280.","DOI":"10.1097\/PSY.0000000000000673"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Ren M, Zhang H, Qi J, Hu A, Jiang Q, Hou Y, et al. An Almond-Based Low Carbohydrate Diet Improves Depression and Glycometabolism in Patients with Type 2 Diabetes through Modulating Gut Microbiota and GLP-1: A Randomized Controlled Trial. Nutrients. 2020; 12: 3036.","DOI":"10.3390\/nu12103036"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Bangasser DA, Cuarenta A. Sex differences in anxiety and depression: circuits and mechanisms. Nature Reviews. Neuroscience. 2021; 22: 674\u2013684.","DOI":"10.1038\/s41583-021-00513-0"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Thomas JT, Thorp JG, Huider F, Grimes PZ, Wang R, Youssef P, et al. Sex-stratified genome-wide association meta-analysis of major depressive disorder. Nature Communications. 2025; 16: 7960.","DOI":"10.1038\/s41467-025-63236-1"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Chausse B, Malorny N, Lewen A, Poschet G, Berndt N, Kann O. Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation. 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