运动诱导巨噬细胞训练免疫耐受改善胰岛素抵抗的研究进展
Research Progress on Exercise-Induced Macrophage Trained Immune Tolerance in Improving Insulin Resistance
DOI: 10.12677/hjbm.2026.164085, PDF,    科研立项经费支持
作者: 王媛媛, 罗 维*：南京体育学院运动健康学院，江苏 南京
关键词: 巨噬细胞；训练免疫；免疫耐受；代谢重编程；胰岛素抵抗；Macrophages； Trained Immunity； Immune Tolerance； Metabolic Reprogramming； Insulin Resistance
摘要: 高脂膳食可通过诱导巨噬细胞的训练免疫(trained immunity, TI)引发胰岛素抵抗(insulin resistance, IR)。通过调节先天免疫细胞对TI的耐受性，阻断IR与TI之间的病理循环，从而减轻由IR继发代谢异常所引起的慢性炎症问题，是防治胰岛素抵抗新的靶向干预点。大量研究表明，运动可以改变巨噬细胞的代谢方式，进而改变其极化表型以达到改善机体代谢、缓解慢性炎症的目的。运动通过促进巨噬细胞氧化磷酸化和线粒体脂肪酸氧化，使巨噬细胞发生代谢重编程，进而产生训练免疫耐受，促使巨噬细胞向M2抗炎表型极化。同时细胞能量代谢增强，葡萄糖摄取量与线粒体功能提高，活性氧的清除增强，这些变化共同推动免疫细胞向抗炎表型转化，并抑制促炎类型的表达，以达到降低机体炎症改善IR的作用。然而，运动促使巨噬细胞免疫耐受发生代谢重编程的具体信号机制尚需进一步明确，同时需要相关实验加以验证。本文旨在探讨运动通过诱导巨噬细胞代谢重编程发生免疫耐受，改善IR的机制及相关信号通路，以期为代谢性疾病的防治开辟新视角。
Abstract: A high-fat diet can induce insulin resistance (IR) by triggering trained immunity (TI) in macrophages. By modulating the tolerance of innate immune cells to TI and blocking the pathological cycle between IR and TI, it is possible to alleviate chronic inflammation caused by metabolism abnormalities secondary to IR, providing a new targeted intervention point for preventing and treating insulin resistance. Numerous studies have shown that exercise can alter macrophage metabolism, thereby changing their polarization phenotype to improve overall metabolism and alleviate chronic inflammation. Exercise promotes metabolic reprogramming in macrophages through oxidative phosphorylation and mitochondrial fatty acid oxidation, which induces trained immunity tolerance and drives macrophages toward an anti-inflammatory M2 phenotype. At the same time, cellular energy metabolism is enhanced, glucose uptake and mitochondrial function are improved, and reactive oxygen species clearance is increased. These changes collectively promote the conversion of immune cells to an anti-inflammatory phenotype and inhibit pro-inflammatory expression, thereby reducing systemic inflammation and improving IR. However, the specific signaling mechanisms by which exercise drives metabolic reprogramming to induce immune tolerance in macrophages still need further clarification, and related experiments are required for validation. This article aims to explore the mechanisms and related signaling pathways by which exercise induces immune tolerance in macrophages through metabolic reprogramming to improve IR, with the goal of providing new perspectives for the prevention and treatment of metabolic diseases.
文章引用：王媛媛, 罗维. 运动诱导巨噬细胞训练免疫耐受改善胰岛素抵抗的研究进展[J]. 生物医学, 2026, 16(4): 829-840. https://doi.org/10.12677/hjbm.2026.164085

参考文献

[1] Samuel, V.T., Petersen, K.F. and Shulman, G.I. (2010) Lipid-Induced Insulin Resistance: Unravelling the Mechanism. The Lancet, 375, 2267-2277.
https://doi.org/10.1016/s0140-6736(10)60408-4
[2] Schenk, S., Saberi, M. and Olefsky, J.M. (2008) Insulin Sensitivity: Modulation by Nutrients and Inflammation. Journal of Clinical Investigation, 118, 2992-3002.
https://doi.org/10.1172/jci34260
[3] Xu, H., Barnes, G.T., Yang, Q., Tan, G., Yang, D., Chou, C.J., et al. (2003) Chronic Inflammation in Fat Plays a Crucial Role in the Development of Obesity-Related Insulin Resistance. Journal of Clinical Investigation, 112, 1821-1830.
https://doi.org/10.1172/jci200319451
[4] Kim, A.B. and Arvanitakis, Z. (2023) Insulin Resistance, Cognition, and Alzheimer Disease. Obesity, 31, 1486-1498.
https://doi.org/10.1002/oby.23761
[5] Hu, T., Liu, C.H., Lei, M., Zeng, Q., Li, L., Tang, H., et al. (2024) Metabolic Regulation of the Immune System in Health and Diseases: Mechanisms and Interventions. Signal Transduction and Targeted Therapy, 9, Article No. 268.
https://doi.org/10.1038/s41392-024-01954-6
[6] Netea, M.G., Schlitzer, A., Placek, K., Joosten, L.A.B. and Schultze, J.L. (2019) Innate and Adaptive Immune Memory: An Evolutionary Continuum in the Host’s Response to Pathogens. Cell Host & Microbe, 25, 13-26.
https://doi.org/10.1016/j.chom.2018.12.006
[7] Bekkering, S., Domínguez-Andrés, J., Joosten, L.A.B., Riksen, N.P. and Netea, M.G. (2021) Trained Immunity: Reprogramming Innate Immunity in Health and Disease. Annual Review of Immunology, 39, 667-693.
https://doi.org/10.1146/annurev-immunol-102119-073855
[8] Hu, Z., Lu, S.H., Lowrie, D.B. and Fan, X.Y. (2022) Trained Immunity: A Yin-Yang Balance. MedComm, 3, e121.
https://doi.org/10.1002/mco2.121
[9] Dong, H., Sun, Y., Nie, L., Cui, A., Zhao, P., Leung, W.K., et al. (2024) Metabolic Memory: Mechanisms and Diseases. Signal Transduction and Targeted Therapy, 9, Article No. 38.
https://doi.org/10.1038/s41392-024-01755-x
[10] Kumar, A., Sundaram, K., Mu, J., Dryden, G.W., Sriwastva, M.K., Lei, C., et al. (2021) High-Fat Diet-Induced Upregulation of Exosomal Phosphatidylcholine Contributes to Insulin Resistance. Nature Communications, 12, Article No. 213.
https://doi.org/10.1038/s41467-020-20500-w
[11] Romeo, M., Silvestrin, A., Senese, G., Di Nardo, F., Napolitano, C., Vaia, P., et al. (2025) From “Traditional” to “Trained” Immunity: Exploring the Novel Frontiers of Immunopathogenesis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Biomedicines, 13, Article 2004.
https://doi.org/10.3390/biomedicines13082004
[12] Hao, D., McBride, M.A., Bohannon, J.K., Hernandez, A., Klein, B., Williams, D.L., et al. (2025) Metabolic Adaptations Driving Innate Immune Memory: Mechanisms and Therapeutic Implications. Journal of Leukocyte Biology, 117, qiaf037.
https://doi.org/10.1093/jleuko/qiaf037
[13] Tang, J., Yan, M., Li, M., Hu, Z. and Zhou, K. (2025) From “Metabolic Storm” to “Immune Paralysis”: The Dynamic Evolution of Macrophages and Metabolism Reprogramming in Ards. Frontiers in Immunology, 16, Article 1738713.
https://doi.org/10.3389/fimmu.2025.1738713
[14] Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A., Wong, J., Nayer, A., et al. (2009) Lean, but Not Obese, Fat Is Enriched for a Unique Population of Regulatory T Cells That Affect Metabolic Parameters. Nature Medicine, 15, 930-939.
https://doi.org/10.1038/nm.2002
[15] Lumeng, C.N. and Saltiel, A.R. (2011) Inflammatory Links between Obesity and Metabolic Disease. Journal of Clinical Investigation, 121, 2111-2117.
https://doi.org/10.1172/jci57132
[16] Witcoski Junior, L., de Lima, J.D., Somensi, A.G., de Souza Santos, L.B., Paschoal, G.L., Uada, T.S., et al. (2024) Metabolic Reprogramming of Macrophages in the Context of Type 2 Diabetes. European Journal of Medical Research, 29, Article No. 497.
https://doi.org/10.1186/s40001-024-02069-y
[17] Krassovskaia, P., Jevtovic, F., Zheng, D., Noone, J., Yeo, R.X., Pino, M.F., et al. (2025) Effects of Habitual Endurance and Resistance Exercise on Insulin Action in Primary Human Skeletal Muscle Stem Cells. Physiological Reports, 13, e70600.
https://doi.org/10.14814/phy2.70600
[18] Coen, P.M., Tanner, C.J., Helbling, N.L., Dubis, G.S., Hames, K.C., Xie, H., et al. (2015) Clinical Trial Demonstrates Exercise Following Bariatric Surgery Improves Insulin Sensitivity. Journal of Clinical Investigation, 125, 248-257.
https://doi.org/10.1172/jci78016
[19] Cheng, W., Guo, K., Zhang, X. and Zhang, K. (2025) Postexercise Immune-Inflammatory Improvement in Type 2 Diabetes Is Associated with Baseline Insulin Resistance. Frontiers in Endocrinology, 16, Article 1679142.
https://doi.org/10.3389/fendo.2025.1679142
[20] Ferreira, A.V., Domínguez-Andrés, J., Merlo Pich, L.M., Joosten, L.A.B. and Netea, M.G. (2024) Metabolic Regulation in the Induction of Trained Immunity. Seminars in Immunopathology, 46, Article No. 7.
https://doi.org/10.1007/s00281-024-01015-8
[21] Daskalaki, M.G., Lapi, I., Hurst, A.E., Al-Qahtani, A., Vergadi, E. and Tsatsanis, C. (2025) Epigenetic and Metabolic Regulation of Macrophage Responsiveness and Memory. The Journal of Immunology, 214, 2812-2821.
https://doi.org/10.1093/jimmun/vkaf135
[22] Faubert, B., Solmonson, A. and DeBerardinis, R.J. (2020) Metabolic Reprogramming and Cancer Progression. Science, 368, eaaw5473.
https://doi.org/10.1126/science.aaw5473
[23] Lin, J., Rao, D., Zhang, M. and Gao, Q. (2024) Metabolic Reprogramming in the Tumor Microenvironment of Liver Cancer. Journal of Hematology & Oncology, 17, Article No. 6.
https://doi.org/10.1186/s13045-024-01527-8
[24] 彭姗姗, 王梦龙, 万军. 肺动脉高压进展过程中巨噬细胞的代谢重编程[J]. 中华老年心脑血管病杂志, 2024, 26(4): 463-465.
[25] Kim, H.G., Rincon, J.C., Efron, P.A. and Maile, R. (2025) DAMP-Driven Trained Immunity: Metabolic and Epigenetic Reprogramming in Critical Illness and Chronic Inflammation. Frontiers in Immunology, 16, Article 1669054.
https://doi.org/10.3389/fimmu.2025.1669054
[26] Netea, M.G., Joosten, L.A.B., Latz, E., Mills, K.H.G., Natoli, G., Stunnenberg, H.G., et al. (2016) Trained Immunity: A Program of Innate Immune Memory in Health and Disease. Science, 352, aaf1098.
https://doi.org/10.1126/science.aaf1098
[27] Bertels, J.C., He, G. and Long, F. (2024) Metabolic Reprogramming in Skeletal Cell Differentiation. Bone Research, 12, Article No. 57.
https://doi.org/10.1038/s41413-024-00374-0
[28] Domblides, C., Lartigue, L. and Faustin, B. (2018) Metabolic Stress in the Immune Function of T Cells, Macrophages and Dendritic Cells. Cells, 7, Article 68.
https://doi.org/10.3390/cells7070068
[29] Lin, C., Chen, Y., Ge, Y., Niu, H., Zhang, X., Jiang, F., et al. (2024) A Bibliometric and Knowledge-Map Analysis of Macrophage Polarization in Insulin Resistance from 1999 to 2023. Immunity, Inflammation and Disease, 12, e70048.
https://doi.org/10.1002/iid3.70048
[30] Holvoet, P. (2023) Aging and Metabolic Reprogramming of Adipose-Derived Stem Cells Affect Molecular Mechanisms Related to Cardiovascular Diseases. Cells, 12, Article 2785.
https://doi.org/10.3390/cells12242785
[31] Röring, R.J., Debisarun, P.A., Botey-Bataller, J., Suen, T.K., Bulut, Ö., Kilic, G., et al. (2024) MMR Vaccination Induces Trained Immunity via Functional and Metabolic Reprogramming of γδ T Cells. Journal of Clinical Investigation, 134, e170848.
https://doi.org/10.1172/jci170848
[32] 罗维, 高文月, 王宇航, 等. 运动改善胰岛素抵抗的新视角: 代谢重编程诱导训练免疫耐受[J]. 生物化学与生物物理进展, 2025, 52(3): 669-680.
[33] Odegaard, J.I., Ricardo-Gonzalez, R.R., Goforth, M.H., Morel, C.R., Subramanian, V., Mukundan, L., et al. (2007) Macrophage-Specific PPARγ Controls Alternative Activation and Improves Insulin Resistance. Nature, 447, 1116-1120.
https://doi.org/10.1038/nature05894
[34] Freemerman, A.J., Johnson, A.R., Sacks, G.N., Milner, J.J., Kirk, E.L., Troester, M.A., et al. (2014) Metabolic Reprogramming of Macrophages. Journal of Biological Chemistry, 289, 7884-7896.
https://doi.org/10.1074/jbc.m113.522037
[35] Iaccarino, G., Franco, D., Sorriento, D., Strisciuglio, T., Barbato, E. and Morisco, C. (2021) Modulation of Insulin Sensitivity by Exercise Training: Implications for Cardiovascular Prevention. Journal of Cardiovascular Translational Research, 14, 256-270.
https://doi.org/10.1007/s12265-020-10057-w
[36] Zhang, H., Chen, T., Ren, J., Xia, Y., Onuma, A., Wang, Y., et al. (2021) Pre-Operative Exercise Therapy Triggers Anti-Inflammatory Trained Immunity of Kupffer Cells through Metabolic Reprogramming. Nature Metabolism, 3, 843-858.
https://doi.org/10.1038/s42255-021-00402-x
[37] Pomeyie, K., Abrokwah, F., Boison, D., Amoani, B., Kyei, F., Adinortey, C.A., et al. (2025) Macrophage Immunometabolism Dysregulation and Inflammatory Disorders. Biomedicine & Pharmacotherapy, 188, Article 118142.
https://doi.org/10.1016/j.biopha.2025.118142
[38] Dionísio, F., Tomas, L. and Schulz, C. (2023) Glycolytic Side Pathways Regulating Macrophage Inflammatory Phenotypes and Functions. American Journal of Physiology-Cell Physiology, 324, C558-C564.
https://doi.org/10.1152/ajpcell.00276.2022
[39] Ma, R., Ji, T., Zhang, H., Dong, W., Chen, X., Xu, P., et al. (2018) A Pck1-Directed Glycogen Metabolic Program Regulates Formation and Maintenance of Memory CD8+ T Cells. Nature Cell Biology, 20, 21-27.
https://doi.org/10.1038/s41556-017-0002-2
[40] Herzig, S. and Shaw, R.J. (2018) AMPK: Guardian of Metabolism and Mitochondrial Homeostasis. Nature Reviews Molecular Cell Biology, 19, 121-135.
https://doi.org/10.1038/nrm.2017.95
[41] Toobian, D., Ghosh, P. and Katkar, G.D. (2021) Parsing the Role of PPARs in Macrophage Processes. Frontiers in Immunology, 12, Article 783780.
https://doi.org/10.3389/fimmu.2021.783780
[42] Ren, J., Li, J., Feng, Y., Shu, B., Gui, Y., Wei, W., et al. (2017) Rictor/Mammalian Target of Rapamycin Complex 2 Promotes Macrophage Activation and Kidney Fibrosis: Rictor in Macrophage Activation and Kidney Fibrosi. The Journal of Pathology, 242, 488-499.
https://doi.org/10.1002/path.4921
[43] Huang, S.C.C., Smith, A.M., Everts, B., et al. (2016) mTORC2-IRF4 Mediated Metabolic Reprograming Is Essential for Macrophage Alternative Activation. Immunity, 45, 817-830.
[44] Oh, H., Park, S., Kang, M., Kim, Y., Lee, E., Kim, D.Y., et al. (2020) Asaronic Acid Inhibited Glucose-Triggered M2-Phenotype Shift through Disrupting the Formation of Coordinated Signaling of Il-4Rα-Tyk2-STAT6 and GLUT1-Akt-mTOR-AMPK. Nutrients, 12, Article 2006.
https://doi.org/10.3390/nu12072006
[45] Leopold Wager, C.M., Arnett, E. and Schlesinger, L.S. (2019) Macrophage Nuclear Receptors: Emerging Key Players in Infectious Diseases. PLOS Pathogens, 15, e1007585.
https://doi.org/10.1371/journal.ppat.1007585
[46] Rückerl, D., Jenkins, S.J., Laqtom, N.N., Gallagher, I.J., Sutherland, T.E., Duncan, S., et al. (2012) Induction of IL-4Rα-Dependent microRNAs Identifies PI3K/Akt Signaling as Essential for IL-4-Driven Murine Macrophage Proliferation in Vivo. Blood, 120, 2307-2316.
https://doi.org/10.1182/blood-2012-02-408252
[47] Rőszer, T. (2015) Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms. Mediators of Inflammation, 2015, Article 816460.
https://doi.org/10.1155/2015/816460
[48] He, L., Jhong, J., Chen, Q., Huang, K., Strittmatter, K., Kreuzer, J., et al. (2021) Global Characterization of Macrophage Polarization Mechanisms and Identification of M2-Type Polarization Inhibitors. Cell Reports, 37, Article 109955.
https://doi.org/10.1016/j.celrep.2021.109955
[49] 杨智, 刘昭前. PPARγ在脂肪细胞分化和糖脂代谢中的作用[J]. 国际病理科学与临床杂志, 2008(1): 14-18.
[50] Hughes, V.A., Fiatarone, M.A., Fielding, R.A., Kahn, B.B., Ferrara, C.M., Shepherd, P., et al. (1993) Exercise Increases Muscle GLUT-4 Levels and Insulin Action in Subjects with Impaired Glucose Tolerance. American Journal of Physiology-Endocrinology and Metabolism, 264, E855-E862.
https://doi.org/10.1152/ajpendo.1993.264.6.e855
[51] Cui, L., Lu, D., Tan, S. and Cao, L. (2025) Comparative Effectiveness of Various Combined Interventions for Type 2 Diabetes and Obesity: A Systematic Review and Network Meta-Analysis. Frontiers in Endocrinology, 16, Article 1462104.
https://doi.org/10.3389/fendo.2025.1462104
[52] Zhu, W., Zhou, Z., Sun, J. and Si, J. (2025) Effects of Exercise Training on Skeletal Muscle Mitochondrial Outcomes in Type 2 Diabetes: A Systematic Review and Meta-Analysis. Frontiers in Physiology, 16, Article 1671926.
https://doi.org/10.3389/fphys.2025.1671926
[53] Lan, Y., Wang, Y., Wu, R. and Lv, P. (2025) Optimizing Exercise for Type 2 Diabetes Management: Comparative Insights from Aerobic, Resistance, Interval and Combined Training Protocols. Metabolites, 15, Article 739.
https://doi.org/10.3390/metabo15110739
[54] Stanley, T.L., Fourman, L.T., Wong, L.P., Sadreyev, R., Billingsley, J.M., Feldpausch, M.N., et al. (2021) Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-Infection and Nonalcoholic Fatty Liver Disease. Clinical Infectious Diseases, 73, 621-630.
https://doi.org/10.1093/cid/ciab019
[55] Pan, Y., Wang, P., Yue, C. and Liu, C. (2025) Effect of Nine Different Exercise Interventions on Insulin Sensitivity in Diabetic Patients: A Systematic Review and Mesh Meta-Analysis. Frontiers in Endocrinology, 16, Article 1409474.
https://doi.org/10.3389/fendo.2025.1409474

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