1932

Abstract

Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we () highlight a leading and early role for adipocytes in promulgating inflammation, () discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and () note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.

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2024-02-12
2024-06-21
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Literature Cited

  1. 1.
    Brestoff JR, Artis D. 2015. Immune regulation of metabolic homeostasis in health and disease. Cell 161:146–60
    [Google Scholar]
  2. 2.
    Crewe C, An YA, Scherer PE. 2017. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Investig. 127:74–82
    [Google Scholar]
  3. 3.
    Mathieu P, Poirier P, Pibarot P, Lemieux I, Despres JP. 2009. Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Hypertension 53:577–84
    [Google Scholar]
  4. 4.
    Stefan N, Haring HU, Hu FB, Schulze MB. 2013. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 1:152–62
    [Google Scholar]
  5. 5.
    Grant RW, Dixit VD. 2015. Adipose tissue as an immunological organ. Obesity 23:512–18
    [Google Scholar]
  6. 6.
    Deng T, Liu J, Deng Y, Minze L, Xiao X et al. 2017. Adipocyte adaptive immunity mediates diet-induced adipose inflammation and insulin resistance by decreasing adipose Treg cells. Nat. Commun. 8:15725
    [Google Scholar]
  7. 7.
    Scheja L, Heeren J. 2019. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat. Rev. Endocrinol. 15:507–24
    [Google Scholar]
  8. 8.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–32
    [Google Scholar]
  9. 9.
    Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. 1995. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269:546–49
    [Google Scholar]
  10. 10.
    Crujeiras AB, Carreira MC, Cabia B, Andrade S, Amil M, Casanueva FF. 2015. Leptin resistance in obesity: an epigenetic landscape. Life Sci. 140:57–63
    [Google Scholar]
  11. 11.
    Zhao S, Zhu Y, Schultz RD, Li N, He Z et al. 2019. Partial leptin reduction as an insulin sensitization and weight loss strategy. Cell Metab. 30:706–19.e6
    [Google Scholar]
  12. 12.
    Faggioni R, Fantuzzi G, Gabay C, Moser A, Dinarello CA et al. 1999. Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am. J. Physiol. 276:R136–42
    [Google Scholar]
  13. 13.
    Takahashi N, Waelput W, Guisez Y. 1999. Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor. J. Exp. Med. 189:207–12
    [Google Scholar]
  14. 14.
    Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C et al. 1996. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. PNAS 93:14564–68
    [Google Scholar]
  15. 15.
    Caldefie-Chezet F, Poulin A, Tridon A, Sion B, Vasson MP. 2001. Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?. J. Leukoc. Biol. 69:414–18
    [Google Scholar]
  16. 16.
    Bruno A, Conus S, Schmid I, Simon HU. 2005. Apoptotic pathways are inhibited by leptin receptor activation in neutrophils. J. Immunol. 174:8090–96
    [Google Scholar]
  17. 17.
    Ottonello L, Gnerre P, Bertolotto M, Mancini M, Dapino P et al. 2004. Leptin as a uremic toxin interferes with neutrophil chemotaxis. J. Am. Soc. Nephrol. 15:2366–72
    [Google Scholar]
  18. 18.
    Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. 1998. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394:897–901
    [Google Scholar]
  19. 19.
    Straub LG, Scherer PE. 2019. Metabolic messengers: adiponectin. Nat. Metab. 1:334–39
    [Google Scholar]
  20. 20.
    Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME et al. 2007. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Investig. 117:2621–37
    [Google Scholar]
  21. 21.
    Chedid P, Hurtado-Nedelec M, Marion-Gaber B, Bournier O, Hayem G et al. 2012. Adiponectin and its globular fragment differentially modulate the oxidative burst of primary human phagocytes. Am. J. Pathol. 180:682–92
    [Google Scholar]
  22. 22.
    Surendar J, Frohberger SJ, Karunakaran I, Schmitt V, Stamminger W et al. 2019. Adiponectin limits IFN-γ and IL-17 producing CD4 T cells in obesity by restraining cell intrinsic glycolysis. Front. Immunol. 10:2555
    [Google Scholar]
  23. 23.
    Hotamisligil GS, Shargill NS, Spiegelman BM. 1993. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259:87–91
    [Google Scholar]
  24. 24.
    Zahorska-Markiewicz B, Janowska J, Olszanecka-Glinianowicz M, Zurakowski A. 2000. Serum concentrations of TNF-α and soluble TNF-α receptors in obesity. Int. J. Obes. Relat. Metab. Disord. 24:1392–95
    [Google Scholar]
  25. 25.
    Stephens JM, Lee J, Pilch PF. 1997. Tumor necrosis factor-α-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J. Biol. Chem. 272:971–76
    [Google Scholar]
  26. 26.
    Ruan H, Miles PD, Ladd CM, Ross K, Golub TR et al. 2002. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-α: implications for insulin resistance. Diabetes 51:3176–88
    [Google Scholar]
  27. 27.
    Wong P, Taillefer D, Lakins J, Pineault J, Chader G, Tenniswood M. 1994. Molecular characterization of human TRPM-2/clusterin, a gene associated with sperm maturation, apoptosis and neurodegeneration. Eur. J. Biochem. 221:917–25
    [Google Scholar]
  28. 28.
    Trougakos IP, Gonos ES. 2006. Regulation of clusterin/apolipoprotein J, a functional homologue to the small heat shock proteins, by oxidative stress in ageing and age-related diseases. Free Radic. Res. 40:1324–34
    [Google Scholar]
  29. 29.
    Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A et al. 2009. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41:1088–93
    [Google Scholar]
  30. 30.
    Bradley D, Blaszczak A, Yin Z, Liu J, Joseph JJ et al. 2019. Clusterin impairs hepatic insulin sensitivity and adipocyte clusterin associates with cardiometabolic risk. Diabetes Care 42:466–75
    [Google Scholar]
  31. 31.
    Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS et al. 1987. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237:402–5
    [Google Scholar]
  32. 32.
    White RT, Damm D, Hancock N, Rosen BS, Lowell BB et al. 1992. Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. J. Biol. Chem. 267:9210–13
    [Google Scholar]
  33. 33.
    Milek M, Moulla Y, Kern M, Stroh C, Dietrich A et al. 2022. Adipsin serum concentrations and adipose tissue expression in people with obesity and type 2 diabetes. Int. J. Mol. Sci. 23:2222
    [Google Scholar]
  34. 34.
    Ohtsuki T, Satoh K, Shimizu T, Ikeda S, Kikuchi N et al. 2019. Identification of adipsin as a novel prognostic biomarker in patients with coronary artery disease. J. Am. Heart Assoc. 8:e013716
    [Google Scholar]
  35. 35.
    Liu L, Chan M, Yu L, Wang W, Qiang L. 2021. Adipsin deficiency does not impact atherosclerosis development in Ldlr−/− mice. Am. J. Physiol. Endocrinol. Metab. 320:E87–92
    [Google Scholar]
  36. 36.
    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR et al. 2001. The hormone resistin links obesity to diabetes. Nature 409:307–12
    [Google Scholar]
  37. 37.
    Huang X, Yang Z. 2016. Resistin's, obesity and insulin resistance: the continuing disconnect between rodents and humans. J. Endocrinol. Investig. 39:607–15
    [Google Scholar]
  38. 38.
    Kloting N, Berndt J, Kralisch S, Kovacs P, Fasshauer M et al. 2006. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem. Biophys. Res. Commun. 339:430–36
    [Google Scholar]
  39. 39.
    Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M et al. 2005. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307:426–30
    [Google Scholar]
  40. 40.
    Dahl TB, Yndestad A, Skjelland M, Oie E, Dahl A et al. 2007. Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization. Circulation 115:972–80
    [Google Scholar]
  41. 41.
    Tan BK, Adya R, Farhatullah S, Lewandowski KC, O'Hare P et al. 2008. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 57:801–8
    [Google Scholar]
  42. 42.
    Zhou H, Zhang Z, Qian G, Zhou J. 2020. Omentin-1 attenuates adipose tissue inflammation via restoration of TXNIP/NLRP3 signaling in high-fat diet-induced obese mice. Fundam. Clin. Pharmacol. 34:721–35
    [Google Scholar]
  43. 43.
    Bradley D, Smith AJ, Blaszczak A, Shantaram D, Bergin SM et al. 2022. Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity. Nat. Commun. 13:5606
    [Google Scholar]
  44. 44.
    McGillicuddy FC, Chiquoine EH, Hinkle CC, Kim RJ, Shah R et al. 2009. Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J. Biol. Chem. 284:31936–44
    [Google Scholar]
  45. 45.
    Deng T, Lyon CJ, Minze LJ, Lin J, Zou J et al. 2013. Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab. 17:411–22
    [Google Scholar]
  46. 46.
    Rocha VZ, Folco EJ, Sukhova G, Shimizu K, Gotsman I et al. 2008. Interferon-γ, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ. Res. 103:467–76
    [Google Scholar]
  47. 47.
    Blaszczak AM, Wright VP, Anandani K, Liu J, Jalilvand A et al. 2019. Loss of antigen presentation in adipose tissue macrophages or in adipocytes, but not both, improves glucose metabolism. J. Immunol. 202:2451–59
    [Google Scholar]
  48. 48.
    Cho KW, Morris DL, DelProposto JL, Geletka L, Zamarron B et al. 2014. An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. Cell Rep. 9:605–17
    [Google Scholar]
  49. 49.
    Tam CS, Viardot A, Clement K, Tordjman J, Tonks K et al. 2010. Short-term overfeeding may induce peripheral insulin resistance without altering subcutaneous adipose tissue macrophages in humans. Diabetes 59:2164–70
    [Google Scholar]
  50. 50.
    Lee KY, Gesta S, Boucher J, Wang XL, Kahn CR. 2011. The differential role of Hif1β/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation. Cell Metab. 14:491–503
    [Google Scholar]
  51. 51.
    Sun K, Tordjman J, Clement K, Scherer PE. 2013. Fibrosis and adipose tissue dysfunction. Cell Metab. 18:470–77
    [Google Scholar]
  52. 52.
    Park J, Scherer PE. 2012. Adipocyte-derived endotrophin promotes malignant tumor progression. J. Clin. Investig. 122:4243–56
    [Google Scholar]
  53. 53.
    Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E et al. 2005. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46:2347–55
    [Google Scholar]
  54. 54.
    Lackey DE, Burk DH, Ali MR, Mostaedi R, Smith WH et al. 2014. Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity. Am. J. Physiol. Endocrinol. Metab. 306:E233–46
    [Google Scholar]
  55. 55.
    Marcelin G, Gautier EL, Clement K. 2022. Adipose tissue fibrosis in obesity: etiology and challenges. Annu. Rev. Physiol. 84:135–55
    [Google Scholar]
  56. 56.
    Lange M, Angelidou G, Ni Z, Criscuolo A, Schiller J et al. 2021. AdipoAtlas: a reference lipidome for human white adipose tissue. Cell Rep. Med. 2:100407
    [Google Scholar]
  57. 57.
    Chaurasia B, Talbot CL, Summers SA. 2020. Adipocyte ceramides—the nexus of inflammation and metabolic disease. Front. Immunol. 11:576347
    [Google Scholar]
  58. 58.
    Tynan GA, Hearnden CH, Oleszycka E, Lyons CL, Coutts G et al. 2014. Endogenous oils derived from human adipocytes are potent adjuvants that promote IL-1α-dependent inflammation. Diabetes 63:2037–50
    [Google Scholar]
  59. 59.
    Holland WL, Knotts TA, Chavez JA, Wang LP, Hoehn KL, Summers SA. 2007. Lipid mediators of insulin resistance. Nutr. Rev. 65:S39–46
    [Google Scholar]
  60. 60.
    Wen H, Gris D, Lei Y, Jha S, Zhang L et al. 2011. Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12:408–15
    [Google Scholar]
  61. 61.
    Watanabe Y, Nagai Y, Honda H, Okamoto N, Yanagibashi T et al. 2019. Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation. FASEB J. 33:11821–35
    [Google Scholar]
  62. 62.
    Huang Z, Xu A. 2021. Adipose extracellular vesicles in intercellular and inter-organ crosstalk in metabolic health and diseases. Front. Immunol. 12:608680
    [Google Scholar]
  63. 63.
    Phoonsawat W, Aoki-Yoshida A, Tsuruta T, Sonoyama K. 2014. Adiponectin is partially associated with exosomes in mouse serum. Biochem. Biophys. Res. Commun. 448:261–66
    [Google Scholar]
  64. 64.
    Eguchi A, Lazic M, Armando AM, Phillips SA, Katebian R et al. 2016. Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress. J. Mol. Med. 94:1241–53
    [Google Scholar]
  65. 65.
    Flaherty SE 3rd, Grijalva A, Xu X, Ables E, Nomani A, Ferrante AW Jr. 2019. A lipase-independent pathway of lipid release and immune modulation by adipocytes. Science 363:989–93
    [Google Scholar]
  66. 66.
    Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M et al. 2017. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450–55
    [Google Scholar]
  67. 67.
    Haneklaus M, Gerlic M, Kurowska-Stolarska M, Rainey AA, Pich D et al. 2012. miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1β production. J. Immunol. 189:3795–99
    [Google Scholar]
  68. 68.
    Pan Y, Hui X, Hoo RLC, Ye D, Chan CYC et al. 2019. Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J. Clin. Investig. 129:834–49
    [Google Scholar]
  69. 69.
    Zhang Y, Mei H, Chang X, Chen F, Zhu Y, Han X. 2016. Adipocyte-derived microvesicles from obese mice induce M1 macrophage phenotype through secreted miR-155. J. Mol. Cell Biol. 8:505–17
    [Google Scholar]
  70. 70.
    Yu Y, Du H, Wei S, Feng L, Li J et al. 2018. Adipocyte-derived exosomal miR-27a induces insulin resistance in skeletal muscle through repression of PPARγ. Theranostics 8:2171–88
    [Google Scholar]
  71. 71.
    Gao J, Li X, Wang Y, Cao Y, Yao D et al. 2020. Adipocyte-derived extracellular vesicles modulate appetite and weight through mTOR signalling in the hypothalamus. Acta Physiol. 228:e13339
    [Google Scholar]
  72. 72.
    Ferrante SC, Nadler EP, Pillai DK, Hubal MJ, Wang Z et al. 2015. Adipocyte-derived exosomal miRNAs: a novel mechanism for obesity-related disease. Pediatr. Res. 77:447–54
    [Google Scholar]
  73. 73.
    O'Brien K, Breyne K, Ughetto S, Laurent LC, Breakefield XO. 2020. RNA delivery by extracellular vesicles in mammalian cells and its applications. Nat. Rev. Mol. Cell Biol. 21:585–606
    [Google Scholar]
  74. 74.
    Rouault C, Pellegrinelli V, Schilch R, Cotillard A, Poitou C et al. 2013. Roles of chemokine ligand-2 (CXCL2) and neutrophils in influencing endothelial cell function and inflammation of human adipose tissue. Endocrinology 154:1069–79
    [Google Scholar]
  75. 75.
    Sartipy P, Loskutoff DJ. 2003. Monocyte chemoattractant protein 1 in obesity and insulin resistance. PNAS 100:7265–70
    [Google Scholar]
  76. 76.
    Engin A. 2017. Adipose tissue hypoxia in obesity and its impact on preadipocytes and macrophages: hypoxia hypothesis. Adv. Exp. Med. Biol. 960:305–26
    [Google Scholar]
  77. 77.
    Ying W, Wollam J, Ofrecio JM, Bandyopadhyay G, El Ouarrat D et al. 2017. Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling. J. Clin. Investig. 127:1019–30
    [Google Scholar]
  78. 78.
    Mariani F, Roncucci L. 2015. Chemerin/chemR23 axis in inflammation onset and resolution. Inflamm. Res. 64:85–95
    [Google Scholar]
  79. 79.
    Liu R, Nikolajczyk BS. 2019. Tissue immune cells fuel obesity-associated inflammation in adipose tissue and beyond. Front. Immunol. 10:1587
    [Google Scholar]
  80. 80.
    Duffaut C, Galitzky J, Lafontan M, Bouloumie A. 2009. Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem. Biophys. Res. Commun. 384:482–85
    [Google Scholar]
  81. 81.
    Hagglof T, Vanz C, Kumagai A, Dudley E, Ortega V et al. 2022. T-bet+ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity. Cell Metab. 34:1121–36
    [Google Scholar]
  82. 82.
    Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J et al. 2009. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15:930–39
    [Google Scholar]
  83. 83.
    Kolodin D, van Panhuys N, Li C, Magnuson AM, Cipolletta D et al. 2015. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab. 21:543–57
    [Google Scholar]
  84. 84.
    Li C, DiSpirito JR, Zemmour D, Spallanzani RG, Kuswanto W et al. 2018. TCR transgenic mice reveal stepwise, multi-site acquisition of the distinctive fat-Treg phenotype. Cell 174:285–99.e12
    [Google Scholar]
  85. 85.
    Winer S, Chan Y, Paltser G, Truong D, Tsui H et al. 2009. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15:921–29
    [Google Scholar]
  86. 86.
    Cipolletta D, Feuerer M, Li A, Kamei N, Lee J et al. 2012. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486:549–53
    [Google Scholar]
  87. 87.
    Varga T, Czimmerer Z, Nagy L. 2011. PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim. Biophys. Acta Mol. Basis Dis. 1812:1007–22
    [Google Scholar]
  88. 88.
    Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A et al. 2011. Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes 60:2954–62
    [Google Scholar]
  89. 89.
    Wu D, Han JM, Yu X, Lam AJ, Hoeppli RE et al. 2019. Characterization of regulatory T cells in obese omental adipose tissue in humans. Eur. J. Immunol. 49:336–47
    [Google Scholar]
  90. 90.
    McLaughlin T, Liu LF, Lamendola C, Shen L, Morton J et al. 2014. T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler. Thromb. Vasc. Biol. 34:2637–43
    [Google Scholar]
  91. 91.
    Gyllenhammer LE, Lam J, Alderete TL, Allayee H, Akbari O et al. 2016. Lower omental t-regulatory cell count is associated with higher fasting glucose and lower β-cell function in adults with obesity. Obesity 24:1274–82
    [Google Scholar]
  92. 92.
    Vijay J, Gauthier MF, Biswell RL, Louiselle DA, Johnston JJ et al. 2020. Single-cell analysis of human adipose tissue identifies depot- and disease-specific cell types. Nat. Metab. 2:97–109
    [Google Scholar]
  93. 93.
    Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P et al. 2017. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170:142–57
    [Google Scholar]
  94. 94.
    Han S, Asoyan A, Rabenstein H, Nakano N, Obst R. 2010. Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery. PNAS 107:20453–58
    [Google Scholar]
  95. 95.
    Tembhre MK, Parihar AS, Sharma VK, Sharma A, Chattopadhyay P, Gupta S. 2015. Alteration in regulatory T cells and programmed cell death 1-expressing regulatory T cells in active generalized vitiligo and their clinical correlation. Br. J. Dermatol. 172:940–50
    [Google Scholar]
  96. 96.
    Mathian A, Parizot C, Dorgham K, Trad S, Arnaud L et al. 2012. Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions. Ann. Rheum. Dis. 71:1227–34
    [Google Scholar]
  97. 97.
    Lowther DE, Goods BA, Lucca LE, Lerner BA, Raddassi K et al. 2016. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 1:e85935
    [Google Scholar]
  98. 98.
    Su X, Wang Q, Guo W, Pei X, Niu Q et al. 2020. Loss of Lkb1 impairs Treg function and stability to aggravate graft-versus-host disease after bone marrow transplantation. Cell. Mol. Immunol. 17:483–95
    [Google Scholar]
  99. 99.
    Yang K, Blanco DB, Neale G, Vogel P, Avila J et al. 2017. Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature 548:602–6
    [Google Scholar]
  100. 100.
    Cipolletta D, Cohen P, Spiegelman BM, Benoist C, Mathis D. 2015. Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARγ effects. PNAS 112:482–87
    [Google Scholar]
  101. 101.
    Maeda Y, Nishikawa H, Sugiyama D, Ha D, Hamaguchi M et al. 2014. Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals. Science 346:1536–40
    [Google Scholar]
  102. 102.
    Han JM, Wu D, Denroche HC, Yao Y, Verchere CB, Levings MK. 2015. IL-33 reverses an obesity-induced deficit in visceral adipose tissue ST2+ T regulatory cells and ameliorates adipose tissue inflammation and insulin resistance. J. Immunol. 194:4777–83
    [Google Scholar]
  103. 103.
    Vasanthakumar A, Moro K, Xin A, Liao Y, Gloury R et al. 2015. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 16:276–85
    [Google Scholar]
  104. 104.
    Spallanzani RG, Zemmour D, Xiao T, Jayewickreme T, Li C et al. 2019. Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors. Sci. Immunol. 4:eaaw3658
    [Google Scholar]
  105. 105.
    Molofsky AB, Savage AK, Locksley RM. 2015. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 42:1005–19
    [Google Scholar]
  106. 106.
    Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M et al. 2008. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler. Thromb. Vasc. Biol. 28:1304–10
    [Google Scholar]
  107. 107.
    Stolarczyk E, Vong CT, Perucha E, Jackson I, Cawthorne MA et al. 2013. Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet. Cell Metab. 17:520–33
    [Google Scholar]
  108. 108.
    Thery C, Ostrowski M, Segura E. 2009. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9:581–93
    [Google Scholar]
  109. 109.
    Sumarac-Dumanovic M, Stevanovic D, Ljubic A, Jorga J, Simic M et al. 2009. Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int. J. Obes. 33:151–56
    [Google Scholar]
  110. 110.
    Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C et al. 2012. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61:2238–47
    [Google Scholar]
  111. 111.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB et al. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–38
    [Google Scholar]
  112. 112.
    Littman DR, Rudensky AY. 2010. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140:845–58
    [Google Scholar]
  113. 113.
    Ip B, Cilfone NA, Belkina AC, DeFuria J, Jagannathan-Bogdan M et al. 2016. Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNFα production. Obesity 24:102–12
    [Google Scholar]
  114. 114.
    Nicholas DA, Proctor EA, Agrawal M, Belkina AC, Van Nostrand SC et al. 2019. Fatty acid metabolites combine with reduced β oxidation to activate Th17 inflammation in human type 2 diabetes. Cell Metab. 30:447–61.e5
    [Google Scholar]
  115. 115.
    Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S et al. 2015. Erratum: De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 21:414
    [Google Scholar]
  116. 116.
    Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE et al. 2013. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210:535–49
    [Google Scholar]
  117. 117.
    Kang YE, Kim HJ, Shong M. 2019. Regulation of systemic glucose homeostasis by T helper type 2 cytokines. Diabetes Metab. J. 43:549–59
    [Google Scholar]
  118. 118.
    Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H et al. 2009. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15:914–20
    [Google Scholar]
  119. 119.
    Jiang E, Perrard XD, Yang D, Khan IM, Perrard JL et al. 2014. Essential role of CD11a in CD8+ T-cell accumulation and activation in adipose tissue. Arterioscler. Thromb. Vasc. Biol. 34:34–43
    [Google Scholar]
  120. 120.
    Nishimura S, Manabe I, Takaki S, Nagasaki M, Otsu M et al. 2013. Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell Metab. 18:759–66
    [Google Scholar]
  121. 121.
    Wang L, Sun P, Wu Y, Wang L. 2021. Metabolic tissue-resident CD8+ T cells: a key player in obesity-related diseases. Obes. Rev. 22:e13133
    [Google Scholar]
  122. 122.
    Xia S, Sha H, Yang L, Ji Y, Ostrand-Rosenberg S, Qi L. 2011. Gr-1+ CD11b+ myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity. J. Biol. Chem. 286:23591–99
    [Google Scholar]
  123. 123.
    Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP et al. 2013. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13:145–49
    [Google Scholar]
  124. 124.
    Ding X, Luo Y, Zhang X, Zheng H, Yang X et al. 2016. IL-33-driven ILC2/eosinophil axis in fat is induced by sympathetic tone and suppressed by obesity. J. Endocrinol. 231:35–48
    [Google Scholar]
  125. 125.
    Nussbaum JC, Van Dyken SJ, von Moltke J, Cheng LE, Mohapatra A et al. 2013. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502:245–48
    [Google Scholar]
  126. 126.
    Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA et al. 2015. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519:242–46
    [Google Scholar]
  127. 127.
    Galle-Treger L, Sankaranarayanan I, Hurrell BP, Howard E, Lo R et al. 2019. Costimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes. Nat. Commun. 10:713
    [Google Scholar]
  128. 128.
    Hams E, Locksley RM, McKenzie AN, Fallon PG. 2013. IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J. Immunol. 191:5349–53
    [Google Scholar]
  129. 129.
    Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB et al. 2015. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160:74–87
    [Google Scholar]
  130. 130.
    O'Rourke RW, Metcalf MD, White AE, Madala A, Winters BR et al. 2009. Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-γ in inflammation in human adipose tissue. Int. J. Obes. 33:978–90
    [Google Scholar]
  131. 131.
    O'Sullivan TE, Rapp M, Fan X, Weizman OE, Bhardwaj P et al. 2016. Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity 45:428–41
    [Google Scholar]
  132. 132.
    Lee BC, Kim MS, Pae M, Yamamoto Y, Eberle D et al. 2016. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab. 23:685–98
    [Google Scholar]
  133. 133.
    Simoni Y, Fehlings M, Kloverpris HN, McGovern N, Koo SL et al. 2018. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity 48:1060
    [Google Scholar]
  134. 134.
    Wensveen FM, Jelencic V, Valentic S, Sestan M, Wensveen TT et al. 2015. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16:376–85
    [Google Scholar]
  135. 135.
    Ballesteros-Pomar MD, Calleja S, Diez-Rodriguez R, Calleja-Fernandez A, Vidal-Casariego A et al. 2014. Inflammatory status is different in relationship to insulin resistance in severely obese people and changes after bariatric surgery or diet-induced weight loss. Exp. Clin. Endocrinol. Diabetes 122:592–96
    [Google Scholar]
  136. 136.
    Hildreth AD, Ma F, Wong YY, Sun R, Pellegrini M, O'Sullivan TE 2021. Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Nat. Immunol. 22:639–53
    [Google Scholar]
  137. 137.
    Winer DA, Winer S, Shen L, Wadia PP, Yantha J et al. 2011. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17:610–17
    [Google Scholar]
  138. 138.
    Shen L, Chng MHY, Alonso MN, Yuan R, Winer DA, Engleman EG. 2015. B-1a lymphocytes attenuate insulin resistance. Diabetes 64:593–603
    [Google Scholar]
  139. 139.
    Glennon-Alty L, Hackett AP, Chapman EA, Wright HL. 2018. Neutrophils and redox stress in the pathogenesis of autoimmune disease. Free Radic. Biol. Med. 125:25–35
    [Google Scholar]
  140. 140.
    Mantovani A, Cassatella MA, Costantini C, Jaillon S. 2011. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11:519–31
    [Google Scholar]
  141. 141.
    Walters N, Zhang J, Rima XY, Nguyen LTH, Germain RN et al. 2021. Analyzing inter-leukocyte communication and migration in vitro: Neutrophils play an essential role in monocyte activation during swarming. Front. Immunol. 12:671546
    [Google Scholar]
  142. 142.
    Elgazar-Carmon V, Rudich A, Hadad N, Levy R. 2008. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J. Lipid Res. 49:1894–903
    [Google Scholar]
  143. 143.
    Mansuy-Aubert V, Zhou QL, Xie X, Gong Z, Huang JY et al. 2013. Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure. Cell Metab. 17:534–48
    [Google Scholar]
  144. 144.
    Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J et al. 2012. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18:1407–12
    [Google Scholar]
  145. 145.
    Wang Q, Xie Z, Zhang W, Zhou J, Wu Y et al. 2014. Myeloperoxidase deletion prevents high-fat diet–induced obesity and insulin resistance. Diabetes 63:4172–85
    [Google Scholar]
  146. 146.
    García-Rubio J, Leon J, Redruello-Romero A, Pavon E, Cozar A et al. 2018. Cytometric analysis of adipose tissue reveals increments of adipocyte progenitor cells after weight loss induced by bariatric surgery. Sci. Rep. 8:15203
    [Google Scholar]
  147. 147.
    Shantaram D, Blaszczak AM, Hoyd R, Smith A, Antwi L et al. 2022. Gut microbiome translocation to visceral adipose tissue promotes recruitment of adipose-specific neutrophils in human obesity. Diabetes 71:1417–P
    [Google Scholar]
  148. 148.
    Moreno-Navarrete JM, Sabater M, Ortega F, Ricart W, Fernandez-Real JM. 2012. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PLOS ONE 7:e37160
    [Google Scholar]
  149. 149.
    Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA et al. 2011. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332:243–47
    [Google Scholar]
  150. 150.
    Rao RR, Long JZ, White JP, Svensson KJ, Lou J et al. 2014. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157:1279–91
    [Google Scholar]
  151. 151.
    Hussaarts L, Garcia-Tardon N, van Beek L, Heemskerk MM, Haeberlein S et al. 2015. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J. 29:3027–39
    [Google Scholar]
  152. 152.
    Bolus WR, Peterson KR, Hubler MJ, Kennedy AJ, Gruen ML, Hasty AH. 2018. Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments. Mol. Metab. 8:86–95
    [Google Scholar]
  153. 153.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. 2003. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Investig. 112:1796–808
    [Google Scholar]
  154. 154.
    Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S et al. 2006. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Investig. 116:115–24
    [Google Scholar]
  155. 155.
    Inouye KE, Shi H, Howard JK, Daly CH, Lord GM et al. 2007. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 56:2242–50
    [Google Scholar]
  156. 156.
    Kirk EA, Sagawa ZK, McDonald TO, O'Brien KD, Heinecke JW. 2008. Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue. Diabetes 57:1254–61 Erratum 2008. Diabetes 57:2552
    [Google Scholar]
  157. 157.
    Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y et al. 2012. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 61:1680–90
    [Google Scholar]
  158. 158.
    Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD et al. 2014. Intestinal permeability—a new target for disease prevention and therapy. BMC Gastroenterol. 14:189
    [Google Scholar]
  159. 159.
    Roedig H, Nastase MV, Wygrecka M, Schaefer L. 2019. Breaking down chronic inflammatory diseases: the role of biglycan in promoting a switch between inflammation and autophagy. FEBS J. 286:2965–79
    [Google Scholar]
  160. 160.
    Tuomi K, Logomarsino JV. 2016. Bacterial lipopolysaccharide, lipopolysaccharide-binding protein, and other inflammatory markers in obesity and after bariatric surgery. Metab. Syndr. Relat. Disord. 14:279–88
    [Google Scholar]
  161. 161.
    Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C et al. 2007. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–72
    [Google Scholar]
  162. 162.
    Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J et al. 2010. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J. Clin. Investig. 120:3466–79
    [Google Scholar]
  163. 163.
    Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. 2006. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Investig. 116:3015–25
    [Google Scholar]
  164. 164.
    Boden G, She P, Mozzoli M, Cheung P, Gumireddy K et al. 2005. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-κB pathway in rat liver. Diabetes 54:3458–65
    [Google Scholar]
  165. 165.
    Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. 2007. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56:16–23
    [Google Scholar]
  166. 166.
    Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B et al. 2010. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59:1648–56
    [Google Scholar]
  167. 167.
    Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M et al. 2007. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int. J. Obes. 31:1420–28
    [Google Scholar]
  168. 168.
    Jackaman C, Radley-Crabb HG, Soffe Z, Shavlakadze T, Grounds MD, Nelson DJ. 2013. Targeting macrophages rescues age-related immune deficiencies in C57 BL/6J geriatric mice. Aging Cell 12:345–57
    [Google Scholar]
  169. 169.
    Blaszczak AM, Jalilvand A, Liu J, Wright VP, Suzo A et al. 2019. Human visceral adipose tissue macrophages are not adequately defined by standard methods of characterization. J. Diabetes Res. 2019:8124563
    [Google Scholar]
  170. 170.
    Li C, Menoret A, Farragher C, Ouyang Z, Bonin C et al. 2019. Single-cell transcriptomics–based MacSpectrum reveals novel macrophage activation signatures in diseases. JCI Insight 4:e126453
    [Google Scholar]
  171. 171.
    Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF et al. 2013. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496:238–42
    [Google Scholar]
  172. 172.
    Stienstra R, Tack CJ, Kanneganti TD, Joosten LA, Netea MG. 2012. The inflammasome puts obesity in the danger zone. Cell Metab. 15:10–18
    [Google Scholar]
  173. 173.
    Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G et al. 2007. Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J. Clin. Investig. 117:1658–69
    [Google Scholar]
  174. 174.
    Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW et al. 2001. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293:1673–77
    [Google Scholar]
  175. 175.
    Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT et al. 2002. A central role for JNK in obesity and insulin resistance. Nature 420:333–36
    [Google Scholar]
  176. 176.
    Shortman K, Liu YJ. 2002. Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2:151–61
    [Google Scholar]
  177. 177.
    Cho KW, Zamarron BF, Muir LA, Singer K, Porsche CE et al. 2016. Adipose tissue dendritic cells are independent contributors to obesity-induced inflammation and insulin resistance. J. Immunol. 197:3650–61
    [Google Scholar]
  178. 178.
    Hernandez-Garcia E, Cueto FJ, Cook ECL, Redondo-Urzainqui A, Charro-Zanca S et al. 2022. Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity. Cell. Mol. Immunol. 19:260–75
    [Google Scholar]
  179. 179.
    Karsunky H, Merad M, Cozzio A, Weissman IL, Manz MG. 2003. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. J. Exp. Med. 198:305–13
    [Google Scholar]
  180. 180.
    Macdougall CE, Wood EG, Loschko J, Scagliotti V, Cassidy FC et al. 2018. Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab. 27:588–601.e4
    [Google Scholar]
  181. 181.
    Stefanovic-Racic M, Yang X, Turner MS, Mantell BS, Stolz DB et al. 2012. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 61:2330–39
    [Google Scholar]
  182. 182.
    Mogilenko DA, Haas JT, L'Homme L, Fleury S, Quemener S et al. 2019. Metabolic and innate immune cues merge into a specific inflammatory response via the UPR. Cell 177:1201–16 Erratum 2019. Cell 178:263
    [Google Scholar]
  183. 183.
    Moraes-Vieira PM, Larocca RA, Bassi EJ, Peron JP, Andrade-Oliveira V et al. 2014. Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells. Eur. J. Immunol. 44:794–806
    [Google Scholar]
  184. 184.
    Li C, Wang G, Sivasami P, Ramirez RN, Zhang Y et al. 2021. Interferon-α-producing plasmacytoid dendritic cells drive the loss of adipose tissue regulatory T cells during obesity. Cell Metab. 33:1610–23.e5
    [Google Scholar]
  185. 185.
    Hannibal TD, Schmidt-Christensen A, Nilsson J, Fransen-Pettersson N, Hansen L, Holmberg D. 2017. Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice. Diabetologia 60:2033–41
    [Google Scholar]
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