nach oben

Diabetologia

Erschienen in:

01.10.2012 | Review

Lymphocytes in obesity-related adipose tissue inflammation

verfasst von: A. Chatzigeorgiou, K. P. Karalis, S. R. Bornstein, T. Chavakis

Erschienen in: Diabetologia | Ausgabe 10/2012

Einloggen, um Zugang zu erhalten

Abstract

Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8⁺ T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4⁺ Th1 and CD4⁺ Th2 cells has been suggested. Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesity-related WAT inflammation and attempt to identify the open questions to be answered by future studies.

Anderson EK, Gutierrez DA, Hasty AH (2010) Adipose tissue recruitment of leukocytes. Curr Opin Lipidol 21:172–177PubMedCrossRef

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 Invest 112:1796–1808PubMed

Wu H, Ghosh S, Perrard XD et al (2007) T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115:1029–1038PubMedCrossRef

Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830PubMed

Fantuzzi G, Faggioni R (2000) Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68:437–446PubMed

Kaminski DA, Randall TD (2010) Adaptive immunity and adipose tissue biology. Trends Immunol 31:384–390PubMedCrossRef

Papathanassoglou E, El-Haschimi K, Li XC, Matarese G, Strom T, Mantzoros C (2006) Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. J Immunol 176:7745–7752PubMed

Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85–97PubMedCrossRef

Lolmede K, Duffaut C, Zakaroff-Girard A, Bouloumie A (2011) Immune cells in adipose tissue: key players in metabolic disorders. Diabetes Metab 37:283–290PubMedCrossRef

10.

Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science 271:665–668PubMedCrossRef

11.

Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389:610–614PubMedCrossRef

12.

Bornstein SR, Abu-Asab M, Glasow A et al (2000) Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. Diabetes 49:532–538PubMedCrossRef

13.

Surmi BK, Hasty AH (2008) Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. Future Lipidol 3:545–556PubMedCrossRef

14.

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 49:1894–1903PubMedCrossRef

15.

Liu J, Divoux A, Sun J et al (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15:940–945PubMedCrossRef

16.

De Taeye BM, Novitskaya T, McGuinness OP et al (2007) Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity. Am J Physiol Endocrinol Metab 293:E713–E725PubMedCrossRef

17.

Arkan MC, Hevener AL, Greten FR et al (2005) IKK-β links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198PubMedCrossRef

18.

Hirosumi J, Tuncman G, Chang L et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336PubMedCrossRef

19.

Matarese G, Procaccini C, De Rosa V, Horvath TL, La Cava A (2010) Regulatory T cells in obesity: the leptin connection. Trends Mol Med 16:247–256PubMedCrossRef

20.

Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedCrossRef

21.

Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604PubMedCrossRef

22.

Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483PubMedCrossRef

23.

Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184PubMedCrossRef

24.

Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686PubMedCrossRef

25.

Ricciardi-Castagnoli P, Granucci F (2002) Opinion: interpretation of the complexity of innate immune responses by functional genomics. Nat Rev Immunol 2:881–889PubMedCrossRef

26.

Stein M, Keshav S, Harris N, Gordon S (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176:287–292PubMedCrossRef

27.

Schenk S, Saberi M, Olefsky JM (2008) Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118:2992–3002PubMedCrossRef

28.

Westcott DJ, Delproposto JB, Geletka LM et al (2009) MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity. J Exp Med 206:3143–3156PubMedCrossRef

29.

Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8:301–309PubMedCrossRef

30.

Feuerer M, Herrero L, Cipolletta D et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939PubMedCrossRef

31.

Nishimura S, Manabe I, Nagasaki M et al (2009) CD8⁺ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920PubMedCrossRef

32.

Winer S, Chan Y, Paltser G et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929PubMedCrossRef

33.

Duffaut C, Zakaroff-Girard A, Bourlier V et al (2009) Interplay between human adipocytes and T lymphocytes in obesity: CCL20 as an adipochemokine and T lymphocytes as lipogenic modulators. Arterioscler Thromb Vasc Biol 29:1608–1614PubMedCrossRef

34.

Rocha VZ, Folco EJ, Sukhova G et al (2008) Interferon-γ, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res 103:467–476PubMedCrossRef

35.

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 384:482–485PubMedCrossRef

36.

Lee YS, Li P, Huh JY et al (2011) Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes 60:2474–2483PubMedCrossRef

37.

Sultan A, Strodthoff D, Robertson AK et al (2009) T cell-mediated inflammation in adipose tissue does not cause insulin resistance in hyperlipidemic mice. Circ Res 104:961–968PubMedCrossRef

38.

Sengenes C, Miranville A, Maumus M, de Barros S, Busse R, Bouloumie A (2007) Chemotaxis and differentiation of human adipose tissue CD34⁺/CD31^– progenitor cells: role of stromal derived factor-1 released by adipose tissue capillary endothelial cells. Stem Cells 25:2269–2276PubMedCrossRef

39.

Herder C, Hauner H, Kempf K, Kolb H, Skurk T (2007) Constitutive and regulated expression and secretion of interferon-gamma-inducible protein 10 (IP-10/CXCL10) in human adipocytes. Int J Obes (Lond) 31:403–410CrossRef

40.

Heller EA, Liu E, Tager AM et al (2006) Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells. Circulation 113:2301–2312PubMedCrossRef

41.

Krinninger P, Brunner C, Ruiz PA et al (2011) Role of the adipocyte-specific NF-ĸB activity in the regulation of IP-10 and T cell migration. Am J Physiol Endocrinol Metab 300:E304–E311PubMedCrossRef

42.

Poggi M, Jager J, Paulmyer-Lacroix O et al (2009) The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes. Diabetologia 52:1152–1163PubMedCrossRef

43.

Rausch ME, Weisberg S, Vardhana P, Tortoriello DV (2008) Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) 32:451–463CrossRef

44.

Kintscher U, Hartge M, Hess K 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 28:1304–1310PubMedCrossRef

45.

Koenen TB, Stienstra R, van Tits LJ et al (2011) The inflammasome and caspase-1 activation: a new mechanism underlying increased inflammatory activity in human visceral adipose tissue. Endocrinology 152:3769–3778PubMedCrossRef

46.

Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19:281–286PubMedCrossRef

47.

Strissel KJ, DeFuria J, Shaul ME, Bennett G, Greenberg AS, Obin MS (2010) T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring) 18:1918–1925CrossRef

48.

O’Rourke RW, Metcalf MD, White AE et al (2009) Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue. Int J Obes (Lond) 33:978–990CrossRef

49.

Zuniga LA, Shen WJ, Joyce-Shaikh B et al (2010) IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 185:6947–6959PubMedCrossRef

50.

Shin JH, Shin DW, Noh M (2009) Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes. Biochem Pharmacol 77:1835–1844PubMedCrossRef

51.

Winer S, Paltser G, Chan Y et al (2009) Obesity predisposes to Th17 bias. Eur J Immunol 39:2629–2635PubMedCrossRef

52.

Cua DJ, Tato CM (2010) Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 10:479–489PubMedCrossRef

53.

Deiuliis J, Shah Z, Shah N et al (2011) Visceral adipose inflammation in obesity is associated with critical alterations in T regulatory cell numbers. PLoS One 6:e16376PubMedCrossRef

54.

Eller K, Kirsch A, Wolf AM et al (2011) Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes 60:2954–2962PubMedCrossRef

55.

Ilan Y, Maron R, Tukpah AM et al (2010) Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc Natl Acad Sci USA 107:9765–9770PubMedCrossRef

56.

Zeyda M, Huber J, Prager G, Stulnig TM (2011) Inflammation correlates with markers of T-cell subsets including regulatory T cells in adipose tissue from obese patients. Obesity (Silver Spring) 19:743–748CrossRef

57.

Liu W, Putnam AL, Xu-Yu Z et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4⁺ T reg cells. J Exp Med 203:1701–1711PubMedCrossRef

58.

Simonetta F, Chiali A, Cordier C et al (2010) Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells. Eur J Immunol 40:2528–2538PubMedCrossRef

59.

De Rosa V, Procaccini C, Cali G et al (2007) A key role of leptin in the control of regulatory T cell proliferation. Immunity 26:241–255PubMedCrossRef

60.

Matarese G, Di Giacomo A, Sanna V et al (2001) Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol 166:5909–5916PubMed

61.

Taleb S, Herbin O, Ait-Oufella H et al (2007) Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis. Arterioscler Thromb Vasc Biol 27:2691–2698PubMedCrossRef

62.

Getz GS, Vanderlaan PA, Reardon CA (2011) Natural killer T cells in lipoprotein metabolism and atherosclerosis. Thromb Haemost 106:814–819PubMedCrossRef

63.

Borg NA, Wun KS, Kjer-Nielsen L et al (2007) CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448:44–49PubMedCrossRef

64.

Mallevaey T, Clarke AJ, Scott-Browne JP et al (2011) A molecular basis for NKT cell recognition of CD1d-self-antigen. Immunity 34:315–326PubMedCrossRef

65.

Ohmura K, Ishimori N, Ohmura Y et al (2010) Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice. Arterioscler Thromb Vasc Biol 30:193–199PubMedCrossRef

66.

Mantell BS, Stefanovic-Racic M, Yang X, Dedousis N, Sipula IJ, O’Doherty RM (2011) Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. PLoS One 6:e19831PubMedCrossRef

67.

Elinav E, Pappo O, Sklair-Levy M et al (2006) Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping. J Pathol 209:121–128PubMedCrossRef

68.

Winer DA, Winer S, Shen L et al (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17:610–617PubMedCrossRef

69.

Lindström P (2007) The physiology of obese–hyperglycemic mice [ob/ob mice]. Scientific World Journal 7:666–685PubMedCrossRef

70.

Palmer G, Aurrand-Lions M, Contassot E et al (2006) Indirect effects of leptin receptor deficiency on lymphocyte populations and immune response in db/db mice. J Immunol 177:2899–2907PubMed

71.

Denroche HC, Levi J, Wideman RD et al (2011) Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 60:1414–1423PubMedCrossRef

72.

Wang MY, Chen L, Clark GO et al (2010) Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci USA 107:4813–4819PubMedCrossRef

73.

Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci USA 107:17391–17396PubMedCrossRef

74.

Oral EA (2012) Leptin for type 1 diabetes: coming onto stage to be (or not?). Pediatr Diabetes 13:68–73PubMedCrossRef

75.

Park JY, Chong AY, Cochran EK et al (2008) Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. J Clin Endocrinol Metab 93:26–31PubMedCrossRef

76.

Tanaka M, Suganami T, Kim-Saijo M et al (2011) Role of central leptin signaling in the starvation-induced alteration of B-cell development. J Neurosci 31:8373–8380PubMedCrossRef

77.

Alberti L, Gilardini L, Girola A, Moro M, Cavagnini F, Invitti C (2007) Adiponectin receptors gene expression in lymphocytes of obese and anorexic patients. Diabetes Obes Metab 9:344–349PubMedCrossRef

78.

van der Weerd K, Dik WA, Schrijver B et al (2012) Morbidly obese human subjects have increased peripheral blood CD4⁺ T cells with skewing toward a Treg- and Th2-dominated phenotype. Diabetes 61:401–408PubMedCrossRef

79.

Monetti M, Levin MC, Watt MJ et al (2007) Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6:69–78PubMedCrossRef

80.

Bostrom P, Wu J, Jedrychowski MP et al (2012) A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–468PubMedCrossRef

81.

Ortega MT, Xie L, Mora S, Chapes SK (2011) Evaluation of macrophage plasticity in brown and white adipose tissue. Cell Immunol 271:124–133PubMedCrossRef

82.

Appay V, van Lier RA, Sallusto F, Roederer M (2008) Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A 73:975–983PubMed

83.

Romagnani S (2006) Regulation of the T cell response. Clin Exp Allergy 36:1357–1366PubMedCrossRef

84.

Romagnani S (2000) T-cell subsets (Th1 versus Th2). Ann Allergy Asthma Immunol 85:9–18PubMedCrossRef

85.

Bluestone JA, Mackay CR, O’Shea JJ, Stockinger B (2009) The functional plasticity of T cell subsets. Nat Rev Immunol 9:811–816PubMedCrossRef

86.

Cipolletta D, Kolodin D, Benoist C, Mathis D (2011) Tissular T_regs: a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Semin Immunol 23:431–437PubMedCrossRef

87.

Godfrey DI, Rossjohn J (2011) New ways to turn on NKT cells. J Exp Med 208:1121–1125PubMedCrossRef

88.

LeBien TW, Tedder TF (2008) B lymphocytes: how they develop and function. Blood 112:1570–1580PubMedCrossRef

Titel: Lymphocytes in obesity-related adipose tissue inflammation
verfasst von: A. Chatzigeorgiou
K. P. Karalis
S. R. Bornstein
T. Chavakis
Publikationsdatum: 01.10.2012
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 10/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2607-0

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Reizdarmsyndrom: Diäten wirksamer als Medikamente

29.04.2024 Reizdarmsyndrom Nachrichten

Bei Reizdarmsyndrom scheinen Diäten, wie etwa die FODMAP-arme oder die kohlenhydratreduzierte Ernährung, effektiver als eine medikamentöse Therapie zu sein. Das hat eine Studie aus Schweden ergeben, die die drei Therapieoptionen im direkten Vergleich analysierte.

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 10/2012

Common polymorphism near the MC4R gene is associated with type 2 diabetes: data from a meta-analysis of 123,373 individuals

Identification of direct forkhead box O1 targets involved in palmitate-induced apoptosis in clonal insulin-secreting cells using chromatin immunoprecipitation coupled to DNA selection and ligation

Impact of transcription factor 7-like 2 (TCF7L2) on pancreatic islet function and morphology in mice and men

Erratum to: Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis

Association between KCNQ1 genetic variants and obesity in Chinese patients with type 2 diabetes

Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes