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Innate immune cells in the adipose tissue

  • Kyoung-Jin Chung
  • Marina Nati
  • Triantafyllos Chavakis
  • Antonios Chatzigeorgiou
Article
  • 501 Downloads

Abstract

Immune cells are present in the adipose tissue (AT) and regulate its function. Under lean conditions, immune cells predominantly of type 2 immunity, including eosinophils, M2-like anti-inflammatory macrophages and innate lymphoid cells 2, contribute to the maintenance of metabolic homeostasis within the AT. In the course of obesity, pro-inflammatory immune cells, such as M1-like macrophages, prevail in the AT. Inflammation in the obese AT is associated with the development of metabolic complications such as insulin resistance, type 2 diabetes and cardiovascular disease. Thus, the immune cell-adipocyte crosstalk in the AT is an important regulator of AT function and systemic metabolism. We discuss herein this crosstalk with a special focus on the role of innate immune cells in AT inflammation and metabolic homeostasis in obesity.

Keywords

Adipose tissue Inflammation Obesity Innate immunity Macrophages Eosinophils Innate lymphoid cells 

Notes

Funding

Supported by grants from the Deutsche Forschungsgemeinschaft (FOR 2599 to AC and IRTG2251 to TC).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

This article does not contain any studies with human participants or animals.

References

  1. 1.
    Chatzigeorgiou A, Chavakis T. Immune cells and metabolism. Handb Exp Pharmacol. 2016;233:221–49.  https://doi.org/10.1007/164_2015_8.PubMedCrossRefGoogle Scholar
  2. 2.
    Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010;316(2):129–39.  https://doi.org/10.1016/j.mce.2009.08.018.PubMedCrossRefGoogle Scholar
  3. 3.
    Zhang M, Hu T, Zhang S, Zhou L. Associations of different adipose tissue depots with insulin resistance: a systematic review and meta-analysis of observational studies. Sci Rep. 2015;5:18495.  https://doi.org/10.1038/srep18495.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Asp Med. 2013;34(1):1–11.  https://doi.org/10.1016/j.mam.2012.10.001.CrossRefGoogle Scholar
  5. 5.
    Alexaki VI, Chavakis T. The role of innate immunity in the regulation of brown and beige adipogenesis. Rev Endocr Metab Disord. 2016;17(1):41–9.  https://doi.org/10.1007/s11154-016-9342-7.PubMedCrossRefGoogle Scholar
  6. 6.
    Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L, Slawik M, et al. Evidence for two types of brown adipose tissue in humans. Nat Med. 2013;19(5):631–4.  https://doi.org/10.1038/nm.3017.PubMedCrossRefGoogle Scholar
  7. 7.
    Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19(10):1252–63.  https://doi.org/10.1038/nm.3361.PubMedCrossRefGoogle Scholar
  8. 8.
    Sanchez-Gurmaches J, Guertin DA. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat Commun. 2014;5:4099.  https://doi.org/10.1038/ncomms5099.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A, et al. Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol. 2014;383(1–2):137–46.  https://doi.org/10.1016/j.mce.2013.12.005.PubMedCrossRefGoogle Scholar
  10. 10.
    Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150(2):366–76.  https://doi.org/10.1016/j.cell.2012.05.016.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Turner JB, Kumar A, Koch CA. The effects of indoor and outdoor temperature on metabolic rate and adipose tissue - the Mississippi perspective on the obesity epidemic. Rev Endocr Metab Disord. 2016;17(1):61–71.  https://doi.org/10.1007/s11154-016-9358-z.PubMedCrossRefGoogle Scholar
  12. 12.
    Siegel-Axel DI, Haring HU. Perivascular adipose tissue: an unique fat compartment relevant for the cardiometabolic syndrome. Rev Endocr Metab Disord. 2016;17(1):51–60.  https://doi.org/10.1007/s11154-016-9346-3.PubMedCrossRefGoogle Scholar
  13. 13.
    Rosenwald M, Perdikari A, Rulicke T, Wolfrum C. Bi-directional interconversion of brite and white adipocytes. Nat Cell Biol. 2013;15(6):659–67.  https://doi.org/10.1038/ncb2740.PubMedCrossRefGoogle Scholar
  14. 14.
    Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab. 2012;15(4):480–91.  https://doi.org/10.1016/j.cmet.2012.03.009.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell. 2009;138(5):961–75.  https://doi.org/10.1016/j.cell.2009.06.046.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Fromme T, Klingenspor M. Uncoupling protein 1 expression and high-fat diets. Am J Physiol Regul Integr Comp Physiol. 2011;300(1):R1–8.  https://doi.org/10.1152/ajpregu.00411.2010.PubMedCrossRefGoogle Scholar
  17. 17.
    Saponaro C, Gaggini M, Carli F, Gastaldelli A. The subtle balance between lipolysis and lipogenesis: a critical point in metabolic homeostasis. Nutrients. 2015;7(11):9453–74.  https://doi.org/10.3390/nu7115475.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Farr OM, Gavrieli A, Mantzoros CS. Leptin applications in 2015: what have we learned about leptin and obesity? Curr Opin Endocrinol Diabetes Obes. 2015;22(5):353–9.  https://doi.org/10.1097/MED.0000000000000184.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kajimura S. Adipose tissue in 2016: Advances in the understanding of adipose tissue biology. Nat Rev Endocrinol. 2017;13(2):69–70.  https://doi.org/10.1038/nrendo.2016.211.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Lago F, Gomez R, Gomez-Reino JJ, Dieguez C, Gualillo O. Adipokines as novel modulators of lipid metabolism. Trends Biochem Sci. 2009;34(10):500–10.  https://doi.org/10.1016/j.tibs.2009.06.008.PubMedCrossRefGoogle Scholar
  21. 21.
    Sahin-Efe A, Katsikeris F, Mantzoros CS. Advances in adipokines. Metabolism. 2012;61(12):1659–65.  https://doi.org/10.1016/j.metabol.2012.09.001.PubMedCrossRefGoogle Scholar
  22. 22.
    Csongradi E, Kaplar M, Nagy B Jr, Koch CA, Juhasz A, Bajnok L, et al. Adipokines as atherothrombotic risk factors in obese subjects: associations with haemostatic markers and common carotid wall thickness. Nutr Metab Cardiovasc Dis. 2017;27(6):571–80.  https://doi.org/10.1016/j.numecd.2017.02.007.PubMedCrossRefGoogle Scholar
  23. 23.
    Engin A. Endothelial dysfunction in obesity. Adv Exp Med Biol. 2017;960:345–79.  https://doi.org/10.1007/978-3-319-48382-5_15.PubMedCrossRefGoogle Scholar
  24. 24.
    McLaughlin T, Ackerman SE, Shen L, Engleman E. Role of innate and adaptive immunity in obesity-associated metabolic disease. J Clin Invest. 2017;127(1):5–13.  https://doi.org/10.1172/JCI88876.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Potthoff MJ. FGF21 and metabolic disease in 2016: A new frontier in FGF21 biology. Nat Rev Endocrinol. 2017;13(2):74–6.  https://doi.org/10.1038/nrendo.2016.206. PubMedCrossRefGoogle Scholar
  26. 26.
    Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, et al. Fetuin-a acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012;18(8):1279–85.  https://doi.org/10.1038/nm.2851.PubMedCrossRefGoogle Scholar
  27. 27.
    Ramage LE, Akyol M, Fletcher AM, Forsythe J, Nixon M, Carter RN, et al. Glucocorticoids acutely increase Brown adipose tissue activity in humans, revealing species-specific differences in UCP-1 regulation. Cell Metab. 2016;24(1):130–41.  https://doi.org/10.1016/j.cmet.2016.06.011.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Chmelar J, Chung KJ, Chavakis T. The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance. Thromb Haemost. 2013;109(3):399–406.  https://doi.org/10.1160/TH12-09-0703.PubMedCrossRefGoogle Scholar
  29. 29.
    Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11(11):738–49.  https://doi.org/10.1038/nri3071.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18(3):363–74.  https://doi.org/10.1038/nm.2627.PubMedCrossRefGoogle Scholar
  31. 31.
    Seijkens T, Kusters P, Chatzigeorgiou A, Chavakis T, Lutgens E. Immune cell crosstalk in obesity: a key role for costimulation? Diabetes. 2014;63(12):3982–91.  https://doi.org/10.2337/db14-0272.PubMedCrossRefGoogle Scholar
  32. 32.
    Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell. 2014;157(6):1292–308.  https://doi.org/10.1016/j.cell.2014.03.066.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell. 2014;157(6):1279–91.  https://doi.org/10.1016/j.cell.2014.03.065.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB, Nussbaum JC, et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell. 2015;160(1–2):74–87.  https://doi.org/10.1016/j.cell.2014.12.011.PubMedCrossRefGoogle Scholar
  35. 35.
    Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. 2011;332(6026):243–7.  https://doi.org/10.1126/science.1201475.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-kit(+)Sca-1(+) lymphoid cells. Nature. 2010;463(7280):540–4.  https://doi.org/10.1038/nature08636.PubMedCrossRefGoogle Scholar
  37. 37.
    Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med. 2013;210(3):535–49.  https://doi.org/10.1084/jem.20121964.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature. 2015;519(7542):242–6.  https://doi.org/10.1038/nature14115.PubMedCrossRefGoogle Scholar
  39. 39.
    Odegaard JI, Chawla A. Type 2 responses at the interface between immunity and fat metabolism. Curr Opin Immunol. 2015;36:67–72.  https://doi.org/10.1016/j.coi.2015.07.003.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117(1):175–84.  https://doi.org/10.1172/JCI29881.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18(9):1407–12.  https://doi.org/10.1038/nm.2885.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Zlotnikov-Klionsky Y, Nathansohn-Levi B, Shezen E, Rosen C, Kagan S, Bar-On L, et al. Perforin-positive dendritic cells exhibit an Immuno-regulatory role in metabolic syndrome and autoimmunity. Immunity. 2015;43(4):776–87.  https://doi.org/10.1016/j.immuni.2015.08.015.PubMedCrossRefGoogle Scholar
  43. 43.
    Wensveen FM, Jelencic V, Valentic S, Sestan M, Wensveen TT, Theurich S, et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol. 2015;16(4):376–85.  https://doi.org/10.1038/ni.3120.PubMedCrossRefGoogle Scholar
  44. 44.
    Bieghs V, Rensen PC, Hofker MH, Shiri-Sverdlov R. NASH and atherosclerosis are two aspects of a shared disease: central role for macrophages. Atherosclerosis. 2012;220(2):287–93.  https://doi.org/10.1016/j.atherosclerosis.2011.08.041.PubMedCrossRefGoogle Scholar
  45. 45.
    Girard J, Lafontan M. Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: visceral adipose tissue production and liver metabolism. Diabetes Metab. 2008;34(5):439–45.  https://doi.org/10.1016/j.diabet.2008.04.002.PubMedCrossRefGoogle Scholar
  46. 46.
    Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science. 2008;322(5907):1539–43.  https://doi.org/10.1126/science.1160794.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014;233(1):104–12.  https://doi.org/10.1016/j.atherosclerosis.2013.12.023.PubMedCrossRefGoogle Scholar
  48. 48.
    Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL, Hugol D, et al. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes. 2006;55(6):1554–61.  https://doi.org/10.2337/db06-0133.PubMedCrossRefGoogle Scholar
  49. 49.
    van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48(2):449–57.  https://doi.org/10.1002/hep.22350.PubMedCrossRefGoogle Scholar
  50. 50.
    Lovren F, Teoh H, Verma S. Obesity and atherosclerosis: mechanistic insights. Can J Cardiol. 2015;31(2):177–83.  https://doi.org/10.1016/j.cjca.2014.11.031.PubMedCrossRefGoogle Scholar
  51. 51.
    Christ A, Gunther P, Lauterbach MAR, Duewell P, Biswas D, Pelka K, et al. Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming. Cell. 2018;172(1–2):162–75 e14.  https://doi.org/10.1016/j.cell.2017.12.013.PubMedCrossRefGoogle Scholar
  52. 52.
    Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. 2015;15(2):104–16.  https://doi.org/10.1038/nri3793.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Yvan-Charvet L, Pagler T, Gautier EL, Avagyan S, Siry RL, Han S, et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science. 2010;328(5986):1689–93.  https://doi.org/10.1126/science.1189731.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M, Grinenko T, et al. Modulation of Myelopoiesis progenitors is an integral component of trained immunity. Cell. 2018;172(1–2):147–61 e12.  https://doi.org/10.1016/j.cell.2017.11.034.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808.  https://doi.org/10.1172/JCI19246.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, et al. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes. 2009;58(11):2574–82.  https://doi.org/10.2337/db08-1475.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Satoh T, Kidoya H, Naito H, Yamamoto M, Takemura N, Nakagawa K, et al. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature. 2013;495(7442):524–8.  https://doi.org/10.1038/nature11930.PubMedCrossRefGoogle Scholar
  58. 58.
    Hui X, Gu P, Zhang J, Nie T, Pan Y, Wu D, et al. Adiponectin enhances cold-induced Browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab. 2015;22(2):279–90.  https://doi.org/10.1016/j.cmet.2015.06.004.PubMedCrossRefGoogle Scholar
  59. 59.
    Ricardo-Gonzalez RR, Red Eagle A, Odegaard JI, Jouihan H, Morel CR, Heredia JE, et al. IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci U S A. 2010;107(52):22617–22.  https://doi.org/10.1073/pnas.1009152108.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kim KH, Kim YH, Son JE, Lee JH, Kim S, Choe MS, et al. Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage. Cell Res. 2017;27(11):1309–26.  https://doi.org/10.1038/cr.2017.126.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Huang Z, Zhong L, Lee JTH, Zhang J, Wu D, Geng L, et al. The FGF21-CCL11 Axis mediates Beiging of white adipose tissues by coupling sympathetic nervous system to type 2 immunity. Cell Metab. 2017;26(3):493–508 e4.  https://doi.org/10.1016/j.cmet.2017.08.003.PubMedCrossRefGoogle Scholar
  62. 62.
    Fabbiano S, Suarez-Zamorano N, Rigo D, Veyrat-Durebex C, Stevanovic Dokic A, Colin DJ, et al. Caloric restriction leads to Browning of white adipose tissue through type 2 immune signaling. Cell Metab. 2016;24(3):434–46.  https://doi.org/10.1016/j.cmet.2016.07.023.PubMedCrossRefGoogle Scholar
  63. 63.
    Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ, van der Heide V, et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med. 2017;23(5):623–30.  https://doi.org/10.1038/nm.4316.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res. 2008;49(7):1562–8.  https://doi.org/10.1194/jlr.M800019-JLR200.PubMedCrossRefGoogle Scholar
  65. 65.
    Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 2008;8(4):301–9.  https://doi.org/10.1016/j.cmet.2008.08.015.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389(6651):610–4.  https://doi.org/10.1038/39335. PubMedCrossRefGoogle Scholar
  67. 67.
    Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12(5):408–15.  https://doi.org/10.1038/ni.2022.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Oh DY, Morinaga H, Talukdar S, Bae EJ, Olefsky JM. Increased macrophage migration into adipose tissue in obese mice. Diabetes. 2012;61(2):346–54.  https://doi.org/10.2337/db11-0860.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447(7148):1116–20.  https://doi.org/10.1038/nature05894.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, et al. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7(6):485–95.  https://doi.org/10.1016/j.cmet.2008.04.002.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, et al. Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest. 2011;121(7):2736–49.  https://doi.org/10.1172/JCI45444.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Eguchi J, Kong X, Tenta M, Wang X, Kang S, Rosen ED. Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization. Diabetes. 2013;62(10):3394–403.  https://doi.org/10.2337/db12-1327.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Shin KC, Hwang I, Choe SS, Park J, Ji Y, Kim JI, et al. Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation. Nat Commun. 2017;8(1):1087.  https://doi.org/10.1038/s41467-017-01232-w. PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, et al. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 2014;19(1):162–71.  https://doi.org/10.1016/j.cmet.2013.11.017.PubMedCrossRefGoogle Scholar
  75. 75.
    Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116(6):1494–505.  https://doi.org/10.1172/JCI26498.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Bruun JM, Lihn AS, Pedersen SB, Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J Clin Endocrinol Metab. 2005;90(4):2282–9.  https://doi.org/10.1210/jc.2004-1696.PubMedCrossRefGoogle Scholar
  77. 77.
    Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006;116(1):115–24.  https://doi.org/10.1172/JCI24335.PubMedCrossRefGoogle Scholar
  78. 78.
    Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes. 2007;56(9):2242–50.  https://doi.org/10.2337/db07-0425.PubMedCrossRefGoogle Scholar
  79. 79.
    Kirk EA, Sagawa ZK, McDonald TO, O'Brien KD, Heinecke JW. Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue [corrected]. Diabetes. 2008;57(5):1254–61.  https://doi.org/10.2337/db07-1061. PubMedCrossRefGoogle Scholar
  80. 80.
    Keophiphath M, Rouault C, Divoux A, Clement K, Lacasa D. CCL5 promotes macrophage recruitment and survival in human adipose tissue. Arterioscler Thromb Vasc Biol. 2010;30(1):39–45.  https://doi.org/10.1161/ATVBAHA.109.197442.PubMedCrossRefGoogle Scholar
  81. 81.
    Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, et al. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes. 2012;61(7):1680–90.  https://doi.org/10.2337/db11-1506.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Chavey C, Lazennec G, Lagarrigue S, Clape C, Iankova I, Teyssier J, et al. CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance. Cell Metab. 2009;9(4):339–49.  https://doi.org/10.1016/j.cmet.2009.03.002.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Ramkhelawon B, Hennessy EJ, Menager M, Ray TD, Sheedy FJ, Hutchison S, et al. Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med. 2014;20(4):377–84.  https://doi.org/10.1038/nm.3467.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Chung KJ, Chatzigeorgiou A, Economopoulou M, Garcia-Martin R, Alexaki VI, Mitroulis I, et al. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat Immunol. 2017;18(6):654–64.  https://doi.org/10.1038/ni.3728.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Hadad N, Burgazliev O, Elgazar-Carmon V, Solomonov Y, Wueest S, Item F, et al. Induction of cytosolic phospholipase a2alpha is required for adipose neutrophil infiltration and hepatic insulin resistance early in the course of high-fat feeding. Diabetes. 2013;62(9):3053–63.  https://doi.org/10.2337/db12-1300.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Mansuy-Aubert V, Zhou QL, Xie X, Gong Z, Huang JY, Khan AR, et al. Imbalance between neutrophil elastase and its inhibitor alpha1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure. Cell Metab. 2013;17(4):534–48.  https://doi.org/10.1016/j.cmet.2013.03.005.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Huang JY, Zhou QL, Huang CH, Song Y, Sharma AG, Liao Z, et al. Neutrophil elastase regulates emergency Myelopoiesis preceding systemic inflammation in diet-induced obesity. J Biol Chem. 2017;292(12):4770–6.  https://doi.org/10.1074/jbc.C116.758748.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Strzepa A, Pritchard KA, Dittel BN. Myeloperoxidase: a new player in autoimmunity. Cell Immunol. 2017;317:1–8.  https://doi.org/10.1016/j.cellimm.2017.05.002. PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Borato DC, Parabocz GC, Ribas JT, Netto HP, Erdmann FC, Wiecheteck LD, et al. Biomarkers in obesity: serum myeloperoxidase and traditional cardiac risk parameters. Exp Clin Endocrinol Diabetes. 2016;124(1):49–54.  https://doi.org/10.1055/s-0035-1565093.PubMedCrossRefGoogle Scholar
  90. 90.
    Wang Q, Xie Z, Zhang W, Zhou J, Wu Y, Zhang M, et al. Myeloperoxidase deletion prevents high-fat diet-induced obesity and insulin resistance. Diabetes. 2014;63(12):4172–85.  https://doi.org/10.2337/db14-0026.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Wu L, Liu YJ. Development of dendritic-cell lineages. Immunity. 2007;26(6):741–50.  https://doi.org/10.1016/j.immuni.2007.06.006.PubMedCrossRefGoogle Scholar
  92. 92.
    Stefanovic-Racic M, Yang X, Turner MS, Mantell BS, Stolz DB, Sumpter TL, et al. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes. 2012;61(9):2330–9.  https://doi.org/10.2337/db11-1523.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Hannibal TD, Schmidt-Christensen A, Nilsson J, Fransen-Pettersson N, Hansen L, Holmberg D. Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice. Diabetologia. 2017;60(10):2033–41.  https://doi.org/10.1007/s00125-017-4341-0.PubMedCrossRefGoogle Scholar
  94. 94.
    Ghosh AR, Bhattacharya R, Bhattacharya S, Nargis T, Rahaman O, Duttagupta P, et al. Adipose recruitment and activation of Plasmacytoid dendritic cells fuel Metaflammation. Diabetes. 2016;65(11):3440–52.  https://doi.org/10.2337/db16-0331.PubMedCrossRefGoogle Scholar
  95. 95.
    Ernst MC, Sinal CJ. Chemerin: at the crossroads of inflammation and obesity. Trends Endocrinol Metab. 2010;21(11):660–7.  https://doi.org/10.1016/j.tem.2010.08.001.PubMedCrossRefGoogle Scholar
  96. 96.
    Cho KW, Zamarron BF, Muir LA, Singer K, Porsche CE, DelProposto JB, et al. Adipose tissue dendritic cells are independent contributors to obesity-induced inflammation and insulin resistance. J Immunol. 2016;197(9):3650–61.  https://doi.org/10.4049/jimmunol.1600820.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kita H. Eosinophils: multifaceted biological properties and roles in health and disease. Immunol Rev. 2011;242(1):161–77.  https://doi.org/10.1111/j.1600-065X.2011.01026.x.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hashiguchi M, Kashiwakura Y, Kojima H, Kobayashi A, Kanno Y, Kobata T. IL-33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells. Eur J Immunol. 2015;45(3):876–85.  https://doi.org/10.1002/eji.201444969.PubMedCrossRefGoogle Scholar
  99. 99.
    Johnson AM, Costanzo A, Gareau MG, Armando AM, Quehenberger O, Jameson JM, et al. High fat diet causes depletion of intestinal eosinophils associated with intestinal permeability. PLoS One. 2015;10(4):e0122195.  https://doi.org/10.1371/journal.pone.0122195.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Withers SB, Forman R, Meza-Perez S, Sorobetea D, Sitnik K, Hopwood T, et al. Eosinophils are key regulators of perivascular adipose tissue and vascular functionality. Sci Rep. 2017;7:44571.  https://doi.org/10.1038/srep44571.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Wang J, Liu R, Wang F, Hong J, Li X, Chen M, et al. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol. 2013;15(12):1455–63.  https://doi.org/10.1038/ncb2867.PubMedCrossRefGoogle Scholar
  102. 102.
    Hart KM, Fabre T, Sciurba JC, Gieseck RL 3rd, Borthwick LA, Vannella KM, et al. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-beta. Sci Transl Med. 2017;9(396):eaal3694.  https://doi.org/10.1126/scitranslmed.aal3694. PubMedCrossRefGoogle Scholar
  103. 103.
    Bolus WR, Peterson KR, Hubler MJ, Kennedy AJ, Gruen ML, Hasty AH. Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments. Mol Metab. 2018;8:86–95.  https://doi.org/10.1016/j.molmet.2017.12.004.PubMedCrossRefGoogle Scholar
  104. 104.
    Eberl G, Colonna M, Di Santo JP, AN MK. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science. 2015;348(6237):aaa6566.  https://doi.org/10.1126/science.aaa6566.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Robinette ML, Fuchs A, Cortez VS, Lee JS, Wang Y, Durum SK, et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat Immunol. 2015;16(3):306–17.  https://doi.org/10.1038/ni.3094.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Hams E, Locksley RM, McKenzie AN, Fallon PG. Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J Immunol. 2013;191(11):5349–53.  https://doi.org/10.4049/jimmunol.1301176.PubMedCrossRefGoogle Scholar
  107. 107.
    Moysidou M, Karaliota S, Kodela E, Salagianni M, Koutmani Y, Katsouda A, et al. CD8+ T cells in beige adipogenesis and energy homeostasis. JCI Insight. 2018;3(5):e95456.  https://doi.org/10.1172/jci.insight.95456.PubMedCentralCrossRefGoogle Scholar
  108. 108.
    Molofsky AB, Van Gool F, Liang HE, Van Dyken SJ, Nussbaum JC, Lee J, et al. Interleukin-33 and interferon-gamma counter-regulate group 2 innate lymphoid cell activation during immune perturbation. Immunity. 2015;43(1):161–74.  https://doi.org/10.1016/j.immuni.2015.05.019.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    O'Sullivan TE, Rapp M, Fan X, Weizman OE, Bhardwaj P, Adams NM, et al. Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity. 2016;45(2):428–41.  https://doi.org/10.1016/j.immuni.2016.06.016.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    O'Sullivan TE, Sun JC, Lanier LL. Natural killer cell memory. Immunity. 2015;43(4):634–45.  https://doi.org/10.1016/j.immuni.2015.09.013.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Kamimura Y, Lanier LL. Homeostatic control of memory cell progenitors in the natural killer cell lineage. Cell Rep. 2015;10(2):280–91.  https://doi.org/10.1016/j.celrep.2014.12.025.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Ballesteros-Pomar MD, Calleja S, Diez-Rodriguez R, Calleja-Fernandez A, Vidal-Casariego A, Nunez-Alonso A, et al. 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. 2014;122(10):592–6.  https://doi.org/10.1055/s-0034-1382035.PubMedCrossRefGoogle Scholar
  113. 113.
    O'Rourke RW, Metcalf MD, White AE, Madala A, Winters BR, Maizlin II, et al. Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue. Int J Obes. 2009;33(9):978–90.  https://doi.org/10.1038/ijo.2009.133.CrossRefGoogle Scholar
  114. 114.
    Simar D, Versteyhe S, Donkin I, Liu J, Hesson L, Nylander V, et al. DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human. Metabolism. 2014;63(9):1188–97.  https://doi.org/10.1016/j.metabol.2014.05.014.PubMedCrossRefGoogle Scholar
  115. 115.
    Guo H, Xu B, Gao L, Sun X, Qu X, Li X, et al. High frequency of activated natural killer and natural killer T-cells in patients with new onset of type 2 diabetes mellitus. Exp Biol Med (Maywood). 2012;237(5):556–62.  https://doi.org/10.1258/ebm.2012.011272.CrossRefGoogle Scholar
  116. 116.
    Kelley DS, Daudu PA, Branch LB, Johnson HL, Taylor PC, Mackey B. Energy restriction decreases number of circulating natural killer cells and serum levels of immunoglobulins in overweight women. Eur J Clin Nutr. 1994;48(1):9–18.PubMedGoogle Scholar
  117. 117.
    Lee BC, Kim MS, Pae M, Yamamoto Y, Eberle D, Shimada T, et al. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab. 2016;23(4):685–98.  https://doi.org/10.1016/j.cmet.2016.03.002.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    O'Rourke RW, Meyer KA, Neeley CK, Gaston GD, Sekhri P, Szumowski M, et al. Systemic NK cell ablation attenuates intra-abdominal adipose tissue macrophage infiltration in murine obesity. Obesity (Silver Spring). 2014;22(10):2109–14.  https://doi.org/10.1002/oby.20823. CrossRefGoogle Scholar
  119. 119.
    Shan B, Wang X, Wu Y, Xu C, Xia Z, Dai J, et al. The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol. 2017;18(5):519–29.  https://doi.org/10.1038/ni.3709.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Paul Langerhans Institute Dresden of the Helmholtz Center MunichUniversity Hospital and Faculty of Medicine, TU DresdenDresdenGermany
  2. 2.German Center for Diabetes Research (DZD e.V.)NeuherbergGermany
  3. 3.Institute for Clinical Chemistry and Laboratory Medicine, Faculty of MedicineTU DresdenDresdenGermany

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