Fucosylated IgG Contributes to Adipose Tissue Dysfunction During Aging

Engineering ›› DOI: 10.1016/j.eng.2025.10.008

review-article

Jingyu Wang ^a^,^#
, Wei Su ^a^,^#
, Haotian Wang ^b^,^#
, Licui Liu ^a
, Jinlong Li ^a^,^c^,^*
, Youxin Wang ^a^,^c^,^d^,^*

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Abstract

Immunoglobulin G (IgG) is recognized as a key regulator of metabolic dysfunction and fibrosis in adipose tissue, and its functional properties are tightly regulated by its glycosylation profile. However, the role of IgG glycosylation in adipose aging remains unclear. Here, we performed transcriptomic and glycoproteomic analyses of epididymal white adipose tissue (eWAT) from young and aged mice. RNA sequencing (RNA-seq) analysis revealed a significant downregulation of adipogenic genes in aged eWAT, accompanied by elevated expression levels of inflammatory and fibrotic markers, which were further validated by quantitative polymerase chain reaction (qPCR). N- and O-glycoproteomic analyses revealed widespread changes in glycosylation. Differentially glycosylated proteins are primarily localized to the extracellular space and participate in innate immune responses, transport and signal transduction, extracellular matrix (ECM)–receptor interaction pathways, and so on. Notably, IgG glycosylation levels were significantly increased in aged mice. Specifically, the N-fucosylation of IgG1, IgG2a, and IgG3 was elevated by 3.1-, 10.4-, and 3.2-fold, respectively, while only IgG2a showed increased O-fucosylation. These findings suggest that N-fucosylation is a common age-related modification across IgG subtypes. Using in vivo models, we further demonstrated that B-cell depletion-induced IgG reduction increased adipogenic and inflammatory gene expression, while the expression of fibrotic markers was suppressed. These effects were reversed upon repletion with either fucosylated or nonfucosylated IgG. Importantly, compared with nonfucosylated IgG, fucosylated IgG exacerbated inflammation and fibrosis but inhibited adipogenesis more strongly. Taken together, our results identify fucosylated IgG as a key mediator of adipose dysfunction during aging and suggest that modulating IgG fucosylation may offer therapeutic potential for age-related metabolic disorders.

Keywords

Immunoglobulin G / Fucosylation / Adipose tissue aging / Glycosylation / Metabolic dysfunction / Fibrosis

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Jingyu Wang, Wei Su, Haotian Wang, Licui Liu, Jinlong Li, Youxin Wang. Fucosylated IgG Contributes to Adipose Tissue Dysfunction During Aging. Engineering DOI:10.1016/j.eng.2025.10.008

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References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	Zhou Z, Yao J, Wu D, Huang X, Wang Y, Li X, et al.Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging.Immunity 2024; 57(3):513-527.e516.

[2]	Li R, Cheng X, Yang Y, Schwebel DC, Ning P, Li L, et al.Global deaths associated with population aging—1990–2019.China CDC Wkly 2023; 5(51):1150-1154.

[3]	Haberman ER, Sarker G, Arus BA, Ziegler KA, Meunier S, Martinez-Sanchez N, et al.Immunomodulatory leptin receptor(+) sympathetic perineurial barrier cells protect against obesity by facilitating brown adipose tissue thermogenesis.Immunity 2024; 57(1):141-152.e5.

[4]	Li B, Li L, Li M, Lam SM, Wang G, Wu Y, et al.Microbiota depletion impairs thermogenesis of brown adipose tissue and browning of white adipose tissue.Cell Rep 2019; 26(10):2720-2737.e5.

[5]	Yu L, Wan Q, Liu Q, Fan Y, Zhou Q, Skowronski AA, et al.IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.Cell Metab 2024; 36(4):793-807.e5.

[6]	Yu Q, Xiao H, Jedrychowski MP, Schweppe DK, Navarrete-Perea J, Knott J, et al.Sample multiplexing for targeted pathway proteomics in aging mice.Proc Natl Acad Sci USA 2020; 117(18):9723-9732.

[7]	Zamboni M, Nori N, Brunelli A, Zoico E.How does adipose tissue contribute to inflammageing?.Exp Gerontol 2021; 143:111162.

[8]	Schaum N, Lehallier B, Hahn O, Palovics R, Hosseinzadeh S, Lee SE, et al.Ageing hallmarks exhibit organ-specific temporal signatures.Nature 2020; 583(7817):596-602.

[9]	Sahu B, Bal NC.Adipokines from white adipose tissue in regulation of whole body energy homeostasis.Biochimie 2023; 204:92-107.

[10]	Green CL, Lamming DW, Fontana L.Molecular mechanisms of dietary restriction promoting health and longevity.Nat Rev Mol Cell Biol 2022; 23(1):56-73.

[11]	Liu S, Zeng M, Wan W, Huang M, Li X, Xie Z, et al.The health-promoting effects and the mechanism of intermittent fasting. J Diabetes Res (2023), Article 4038546

[12]	Xu L, Ma X, Verma N, Perie L, Pendse J, Shamloo S, et al.PPARgamma agonists delay age-associated metabolic disease and extend longevity.Aging Cell 2020; 19(11):e13267.

[13]	Wang L, Wang B, Gasek NS, Zhou Y, Cohn RL, Martin DE, et al.Targeting p21(cip1) highly expressing cells in adipose tissue alleviates insulin resistance in obesity.Cell Metab 2022; 34(1):186.

[14]	Wang W.Glycomedicine: the current state of the art.Engineering 2023; 26:12-15.

[15]	Wang W, Yang BF.The glycome and glycomedicine.Engineering 2023; 26:1-2.

[16]	Wu Y, Zhang Z, Chen L, Sun S.Immunoglobulin g glycosylation and its alterations in aging-related diseases.Acta Biochim Biophy Sin 2024; 56(8):1221-1233.

[17]	Ercoli G, Ramos-Sevillano E, Nakajima R, de RR Assis, Jasinskas A, Goldblatt D, et al.The influence of b cell depletion therapy on naturally acquired immunity to streptococcus pneumoniae.Front Immunol 2020; 11:611661.

[18]	Peng J, Vongpatanasin W, Sacharidou A, Kifer D, Yuhanna IS, Banerjee S, et al.Supplementation with the sialic acid precursor N-acetyl-D-mannosamine breaks the link between obesity and hypertension.Circulation 2019; 140(24):2005-2018.

[19]	Luo C, Chen S, Xu N, Wang C, Sai WB, Zhao W, et al.Glycoengineering of pertuzumab and its impact on the pharmacokinetic/pharmacodynamic properties.Sci Rep 2017; 7(1):46347.

[20]	Zhou Q, Wan Q, Jiang Y, Liu J, Qiang L, Sun L.A landscape of murine long non-coding RNAs reveals the leading transcriptome alterations in adipose tissue during aging.Cell Rep 2020; 31(8):107694.

[21]	Sun K, Tordjman J, Cl Kément, Scherer PE.Fibrosis and adipose tissue dysfunction.Cell Metab 2013; 18(4):470-477.

[22]	Palmer AK, Kirkland JL.Aging and adipose tissue: potential interventions for diabetes and regenerative medicine.Exp Gerontol 2016; 86:97-105.

[23]	Nguyen TT, Corvera S.Adipose tissue as a linchpin of organismal ageing.Nat Metab 2024; 6(5):793-807.

[24]	Ahmed B, Farb MG, Gokce N.Cardiometabolic implications of adipose tissue aging.Obes Rev 2024; 25(11):e13806.

[25]	Whytock KL, Divoux A, Sun Y, Pino MF, Yu G, Jin CA, et al.Aging human abdominal subcutaneous white adipose tissue at single cell resolution.Aging Cell 2024; 23(11):e14287.

[26]	Schjoldager KT, Narimatsu Y, Joshi HJ, Clausen H.Global view of human protein glycosylation pathways and functions.Nat Rev Mol Cell Biol 2020; 21(12):729-749.

[27]	Chatham JC, Patel RP.Protein glycosylation in cardiovascular health and disease.Nat Rev Cardiol 2024; 21(8):525-544.

[28]	Wu Y, Zhang Z, Xu Y, Zhang Y, Chen L, Zhang Y, et al.A high-resolution n-glycoproteome landscape of aging mouse ovary.Redox Biol 2025; 81:103584.

[29]	Franzka P, Kruger L, Schurig MK, Olecka M, Hoffmann S, Blanchard V, et al.Altered glycosylation in the aging heart.Front Mol Biosci 2021; 8:673044.

[30]	Steigmeyer AD, Lowery SC, Rangel-Angarita V, Malaker SA.Decoding extracellular protein glycosylation in human health and disease.Annu Rev Anal Chem 2025; 18(1):241-264.

[31]	Meng XN, Cao WJ, Liu D, Elijah IM, Xing WJ, Hou HF, et al.Bidirectional causality between immunoglobulin G N-glycosylation and metabolic traits: a mendelian randomization study.Engineering 2023; 26:2674-2688.

[32]	Wang Y, Klari Lć, Yu X, Thaqi K, Dong J, Novokmet M, et al.The association between glycosylation of immunoglobulin g and hypertension: a multiple ethnic cross-sectional study.Medicine 2016; 95(17):e3379.

[33]	Liu D, Chu X, Wang H, Dong J, Ge SQ, Zhao ZY, et al.The changes of immunoglobulin g n-glycosylation in blood lipids and dyslipidaemia.J Transl Med 2018; 16(1):235.

[34]	Meng X, Wang F, Gao X, Wang B, Xu X, Wang Y, et al.Association of IgG N-glycomics with prevalent and incident type 2 diabetes mellitus from the paradigm of predictive, preventive, and personalized medicine standpoint.EPMA J 2023; 14(1):1-20.

[35]	Wu ZY, Guo Z, Zheng YL, Wang YT, Zhang HP, Pan HY, et al.IgG N-glycosylation cardiovascular age tracks cardiovascular risk beyond calendar age.Engineering 2023; 26:99-107.

[36]	Streng BMM, Van J Coillie, Wildenbeest JG, Binnendijk RS, Smits G, den G Hartog, et al.IgG1 glycosylation highlights premature aging in Down syndrome.Aging Cell 2024; 23(7):e14167.

[37]	Sjowall C, Zapf J, von S Lohneysen, Magorivska I, Biermann M, Janko C, et al.Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus.Lupus 2015; 24(6):569-581.

[38]	Trzos S, Link-Lenczowski P, Sokolowski G, Pochec E.Changes of IgG N-glycosylation in thyroid autoimmunity: the modulatory effect of methimazole in graves’ disease and the association with the severity of inflammation in Hashimoto’s thyroiditis.Front Immunol 2022; 13:841710.

[39]	Greto VL, Cvetko A, Stambuk T, Dempster NJ, Kifer D, Deris H, et al.Extensive weight loss reduces glycan age by altering IgG N-glycosylation.Int J Obes 2021; 45(7):1521-1531.

[40]	Li X, Wang H, Zhu Y, Cao W, Song M, Wang Y, et al.Heritability enrichment of immunoglobulin G N-glycosylation in specific tissues.Front Immunol 2021; 12:741705.

[41]	Hagglof T, Vanz C, Kumagai A, Dudley E, Ortega V, Siller M, et al.T-bet⁺ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity.Cell Metab 2022; 34(8):1121-1136.e6.

[42]	Wongtrakul-Kish K, Herbert BR, Packer NH.Bisecting GLCNAC protein N-glycosylation is characteristic of human adipogenesis.J Proteome Res 2021; 20(2):1313-1327.

[43]	Vanhooren V, Dewaele S, Kuro OM, Taniguchi N, Dolle L, van LA Grunsven, et al.Alteration in N-glycomics during mouse aging: a role for Fut8.Aging Cell 2011; 10(6):1056-1066.

[44]	Yuan W, Sanda M, Wu J, Koomen J, Goldman R.Quantitative analysis of immunoglobulin subclasses and subclass specific glycosylation by LC-MS-MRM in liver disease.J Proteomics 2015; 116:11624-11633.

[45]	Chen CL, Hsu JC, Lin CW, Wang CH, Tsai MH, Wu CY, et al.Crystal structure of a homogeneous IgG-Fc glycoform with the N-glycan designed to maximize the antibody dependent cellular cytotoxicity.ACS Chem Biol 2017; 12(5):1335-1345.

[46]	Biermann MH, Griffante G, Podolska MJ, Boeltz S, Sturmer J, Munoz LE, et al.Sweet but dangerous—the role of immunoglobulin g glycosylation in autoimmunity and inflammation.Lupus 2016; 25(8):934-942.

[47]	Le NP, Bowden TA, Struwe WB, Crispin M.Immune recruitment or suppression by glycan engineering of endogenous and therapeutic antibodies.Biochim Biophys Acta Gen Subj 2016; 1860(8):1655-1668.

[48]	Shin E, Bak SH, Park T, Kim JW, Yoon SR, Jung H, et al.Understanding NK cell biology for harnessing NK cell therapies: targeting cancer and beyond.Front Immunol 2023; 14:1192907.

[49]	Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, et al.Cellular senescence mediates fibrotic pulmonary disease.Nat Commun 2017; 8(1):14532.

[50]	Wohner M, Nimmerjahn F.Cytotoxic IgG: mechanisms, functions, and applications.Immunity 2025; 58(6):1378-1395.

[51]	Meng X, Wang B, Xu X, Song M, Hou H, Wang W, et al.Glycomic biomarkers are instrumental for suboptimal health status management in the context of predictive, preventive, and personalized medicine.EPMA J 2022; 13(2):195-207.

[52]	Liu D, Li Q, Dong J, Li D, Xu X, Xing W, et al.The association between normal BMI with central adiposity and proinflammatory potential immunoglobulin G N-glycosylation.Diabetes Metab Syndr Obes 2019; 12:2373-2385.

[53]	Grav LM, Lee JS, Gerling S, Kallehauge TB, Hansen AH, Kol S, et al.One-step generation of triple knockout CHO cell lines using CRISPR/Cas9 and fluorescent enrichment.Biotechnol J 2015; 10(9):1446-1456.

[54]	Butler M, Meneses-Acosta A.Recent advances in technology supporting biopharmaceutical production from mammalian cells.Appl Microbiol Biotechnol 2012; 96(4):885-894.

[55]	Pan Q, Xie Y, Zhang Y, Guo X, Wang J, Liu M, et al.EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses.Nat Commun 2024; 15(1):652.

[56]	Nimmerjahn F, Vidarsson G, Cragg MS.Effect of posttranslational modifications and subclass on IgG activity: from immunity to immunotherapy.Nat Immunol 2023; 24(8):1244-1255.

[57]	Bhargava R, Upadhyay R, Zhao C, Katakam P, Wenderfer S, Chen J, et al.Aberrant glycosylation of IgG in children with active lupus nephritis alters podocyte metabolism and causes podocyte injury.Arthritis Rheumatol 2025; 77(10):1421-1432.

[58]	Alfaras I, Ejima K, Vieira C Ligo Teixeira, Di C Germanio, Mitchell SJ, Hamilton S, et al.Empirical versus theoretical power and type I error (false-positive) rates estimated from real murine aging research data.Cell Rep 2021; 36(7):109560.