儿童肥胖及相关代谢性疾病(如胰岛素抵抗、脂代谢紊乱、代谢相关脂肪性肝病等)已成为重要公共卫生问题。既往研究往往聚焦于单一器官或组织层面的改变,难以解析肥胖进程中多组织器官的动态变化。儿童肥胖相关代谢紊乱本质上是脂肪组织功能障碍引发的、涉及免疫系统失调和代谢稳态失衡等多系统深度交互的复杂网络性疾病。本文系统综述了当前儿童肥胖与代谢性疾病之间关联机制的研究进展,重点聚焦三大病理路径:免疫细胞介导的慢性炎症、代谢物积累与代谢重编程、以及脂肪组织生物力学微环境异常。研究显示,在肥胖状态下,T细胞、B细胞及巨噬细胞在脂肪组织中活性改变,构建免疫-代谢的双向反馈回路;支链氨基酸和非酯化脂肪酸等代谢物可干扰胰岛素信号传导,引发胰岛素抵抗;而细胞外基质硬化及力学应激增强则进一步激活炎症通路,形成“免疫-代谢-基质”复合网络。儿童肥胖相关代谢异常具有早发、多器官、长期遗留等特点。未来应加强多组学技术整合与多系统互作机制研究,推动个体化干预策略的临床转化,以改善儿童肥胖相关代谢疾病的防治效果。
Abstract
Childhood obesity and its associated metabolic diseases (e.g., insulin resistance, dyslipidemia, metabolic dysfunction-associated fatty liver disease, etc.) have emerged as a significant public health concern.Previous studies often focused on changes at the single organ or tissue level, making it challenging to elucidate the dynamic changes across multiple tissues and organs during the progression of obesity.Metabolic disorders related to childhood obesity are essentially complex network diseases initiated by the dysfunction or collapse of adipose tissue function, involving deep interactions among multiple systems such as immune system dysregulation and the collapse of metabolic homeostasis.This study systematically reviews current research progress on the mechanisms underlying the association between childhood obesity and metabolic diseases, with a focus on three key pathological pathways: chronic inflammation mediated by immune cells, metabolite accumulation and metabolic reprogramming, and abnormal changes in adipose tissue biomechanics microenvironment.It is reported that T cells, B cells, and macrophages exhibit altered activity in adipose tissue with obesity, establishing a bidirectional feedback loop between immunity and metabolism.Metabolites such as branched-chain amino acids and non-esterified fatty acids can interfere with insulin signaling, inducing insulin resistance.Besides, extracellular matrix stiffening and increased mechanical stress further activate inflammatory pathways, forming an immune-metabolic-matrix composite network.Metabolic abnormalities associated with childhood obesity are characterized by early onset, multi-organ involvement, and long-term persistence.Future research should enhance the integration of multi-omics technologies with investigations into the mechanisms of multi-system interactions, promoting the clinical translation of personalized intervention strategies, and thereby improving the prevention and treatment outcomes of childhood obesity-related metabolic diseases.
关键词
儿童肥胖 /
代谢性疾病 /
免疫细胞 /
代谢重编程 /
细胞生物力学
Key words
childhood obesity /
metabolic diseases /
immune cells /
metabolic reprogramming /
cellular biomechanics
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Münte E, Zhang X, Khurana A, et al.Prevalence of extremely severe obesity and metabolic dysfunction among US children and adolescents[J].JAMA Netw Open, 2025, 8(7): e2521170.
[2] Guo DF, Lin Z, Wu Y, et al.The BBSome in POMC and AgRP neurons is necessary for body weight regulation and sorting of metabolic receptors[J].Diabetes, 2019, 68(8): 1591-1603.
[3] Muglia LJ, Benhalima K, Tong S, et al.Maternal factors during pregnancy influencing maternal, fetal, and childhood outcomes[J].BMC Med, 2022, 20(1): 418.
[4] Hoffman DJ, Powell TL, Barrett ES, et al.Developmental origins of metabolic diseases[J].Physiol Rev, 2021, 101(3): 739-795.
[5] Du W, Zou ZP, Ye BC, et al.Gut microbiota and associated metabolites: Key players in high-fat diet-induced chronic diseases[J].Gut Microbes, 2025, 17(1): 2494703.
[6] Grilo CM, Lydecker JA, Fineberg SK, et al.Naltrexone-bupropion and behavior therapy, alone and combined, for binge-eating disorder: Randomized double-blind placebo-controlled trial[J].Am J Psychiatry, 2022, 179(12): 927-937.
[7] Aquilano K, Ceci V, Gismondi A, et al.Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts[J].Commun Biol, 2019, 2: 317.
[8] Nishimura S, Manabe I, Nagasaki M, et al.CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity[J].Nat Med, 2009, 15(8): 914-920.
[9] Yu W, Li C, Zhang D, et al.Advances in T cells based on inflammation in metabolic diseases[J].Cells, 2022, 11(22): 3554.
[10] Rogers J, Hakki A, Perkins I, et al.Legionella pneumophila infection up-regulates dendritic cell Toll-like receptor 2 (TLR2)/TLR4 expression and key maturation markers[J].Infect Immun, 2007, 75(6): 3205-3208.
[11] Winer DA, Winer S, Shen L, et al.B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies[J].Nat Med, 2011, 17(5): 610-617.
[12] DeFuria J, Belkina AC, Jagannathan-Bogdan M, et al.B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile[J].Proc Natl Acad Sci U S A, 2013, 110(13): 5133-5138.
[13] Pearson JA, Ding H, Hu C, et al.IgM-associated gut bacteria in obesity and type 2 diabetes in C57BL/6 mice and humans[J].Diabetologia, 2022, 65(8): 1398-1411.
[14] Harmon DB, Srikakulapu P, Kaplan JL, et al.Protective role for B-1b B cells and IgM in obesity-associated inflammation, glucose intolerance, and insulin resistance[J].Arterioscler Thromb Vasc Biol, 2016, 36(4): 682-691.
[15] Samiea A, Celis G, Yadav R, et al.B cells in non-lymphoid tissues[J].Nat Rev Immunol, 2025, 25(7): 483-496.
[16] Lumeng CN, Bodzin JL, Saltiel AR.Obesity induces a phenotypic switch in adipose tissue macrophage polarization[J].J Clin Invest, 2007, 117(1): 175-184.
[17] Liu H, Wang P, Xu F, et al.The hydrophilic metabolite UMP alleviates obesity traits through a HIF2α-ACER2-ceramide signaling axis[J].Adv Sci, 2024, 11(21): e2309525.
[18] Virtue S, Vidal-Puig A.Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome--an allostatic perspective[J].Biochim Biophys Acta, 2010, 1801(3): 338-349.
[19] Corrigendum for “Assessment of β cell mass and function by AIRmax and intravenous glucose in high-risk subjects for type 1 diabetes”[J].J Clin Endocrinol Metab, 2018, 103(4): 1653.
[20] Wen H, Gris D, Lei Y, et al.Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling[J].Nat Immunol, 2011, 12(5): 408-415.
[21] Finucane OM, Lyons CL, Murphy AM, et al.Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1β secretion and insulin resistance despite obesity[J].Diabetes, 2015, 64(6): 2116-2128.
[22] Lynch CJ, Adams SH.Branched-chain amino acids in metabolic signalling and insulin resistance[J].Nat Rev Endocrinol, 2014, 10(12): 723-736.
[23] Hernández-Alvarez MI, Díaz-Ramos A, Berdasco M, et al.Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism[J].Sci Rep, 2017, 7(1): 13850.
[24] White PJ, Lapworth AL, An J, et al.Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export[J].Mol Metab, 2016, 5(7): 538-551.
[25] Eirin A, Thaler R, Glastetter LM, et al.Obesity-driven mitochondrial dysfunction in human adipose tissue-derived mesenchymal stem/stromal cells involves epigenetic changes[J].Cell Death Dis, 2024, 15(6): 387.
[26] Hartsoe P, Holguin F, Chu HW.Mitochondrial dysfunction and metabolic reprogramming in obesity and asthma[J].Int J Mol Sci, 2024, 25(5): 2944.
[27] Zhou T, Pan J, Xu K, et al.Single-cell transcriptomics in MI identify Slc25a4 as a new modulator of mitochondrial malfunction and apoptosis-associated cardiomyocyte subcluster[J].Sci Rep, 2024, 14(1): 9274.
[28] González-Domínguez Á, Belmonte T, González-Domínguez R.Childhood obesity, metabolic syndrome, and oxidative stress: microRNAs go on stage[J].Rev Endocr Metab Disord, 2023, 24(6): 1147-1164.
[29] Chen ZJ, Das SS, Kar A, et al.Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue[J].Nat Genet, 2025: 1-12.
[30] Badr M, El-Rabaa G, Freiha M, et al.Endocrine consequences of childhood obesity: A narrative review[J].Front Endocrinol, 2025, 16: 1584861.
[31] Wen X, Zhang B, Wu B, et al.Signaling pathways in obesity: Mechanisms and therapeutic interventions[J].Signal Transduct Target Ther, 2022, 7(1): 298.
[32] Musale V, Wasserman DH, Kang L.Extracellular matrix remodelling in obesity and metabolic disorders[J].Life Metab, 2023, 2(4): load021.
[33] Mujkić R, Šnajder Mujkić D, Ilić I, et al.Early childhood fat tissue changes-adipocyte morphometry, collagen deposition, and expression of CD163+ cells in subcutaneous and visceral adipose tissue of male children[J].Int J Environ Res Public Health, 2021, 18(7): 3627.
[34] Jiang Y, Guo JQ, Wu Y, et al.Excessive or sustained endoplasmic reticulum stress: One of the culprits of adipocyte dysfunction in obesity[J].Ther Adv Endocrinol Metab, 2024, 15: 20420188241282707.
[35] Su É, Villard C, Manneville JB.Mitochondria: At the crossroads between mechanobiology and cell metabolism[J].Biol Cell, 2023, 115(9): e2300010.
[36] Hma J, Ne S, Dl Z, et al.Exercise inhibits NLRP3 inflammasome activation in obese mice via the anti-inflammatory effect of meteorin-like[J].Cells, 2021, 10(12): 3480.
[37] Shook BA, Wasko RR, Mano O, et al.Dermal adipocyte lipolysis and myofibroblast conversion are required for efficient skin repair[J].Cell Stem Cell, 2020, 26(6): 880-895.e6.
基金
国家重点研发计划(2021YFC2701900, 2021YFC2701903);国家自然科学基金(82170869)
PDF(498 KB)
