Skip to main content

Advertisement

SpringerLink
Log in

Immune cells in adipose tissue microenvironment under physiological and obese conditions

  • Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

This review will focus on the immune cells in adipose tissue microenvironment and their regulatory roles in metabolic homeostasis of adipose tissue and even the whole body under physiological and obese conditions.

Methods

This review used PubMed searches of current literature to examine adipose tissue immune cells and cytokines, as well as the complex interactions between them.

Results

Aside from serving as a passive energy depot, adipose tissue has shown specific immunological function. Adipose tissue microenvironment is enriched with a large number of immune cells and cytokines, whose physiological regulation plays a crucial role for metabolic homeostasis. However, obesity causes pro-inflammatory alterations in these adipose tissue immune cells, which have detrimental effects on metabolism and increase the susceptibility of individuals to the obesity related diseases.

Conclusions

Adipose tissue microenvironment is enriched with various immune cells and cytokines, which regulate metabolic homeostasis of adipose tissue and even the whole body, whether under physiological or obese conditions. Targeting key immune cells and cytokines in adipose tissue microenvironment for obesity treatment becomes an attractive research point.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. G.S. Hotamisligil, N.S. Shargill, B.M. Spiegelman, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993). https://doi.org/10.1126/science.7678183

    Article  CAS  PubMed  Google Scholar 

  2. H. Xu, G.T. Barnes, Q. Yang, G. Tan, D. Yang, C.J. Chou, J. Sole, A. Nichols, J.S. Ross, L.A. Tartaglia, H. Chen, Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003). https://doi.org/10.1172/JCI19451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. S.P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R.L. Leibel, A.W. Ferrante, Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003). https://doi.org/10.1172/JCI19246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. A. Schäffler, J. Schölmerich, B. Salzberger, Adipose tissue as an immunological organ: toll-like receptors, C1q/TNFs and CTRPs. Trends Immunol. 28, 393–399 (2007). https://doi.org/10.1016/j.it.2007.07.003

    Article  CAS  PubMed  Google Scholar 

  5. R.W. Grant, V.D. Dixit, Adipose tissue as an immunological organ. Obesity (Silver Spring) 23, 512–518 (2015). https://doi.org/10.1002/oby.21003

    Article  CAS  PubMed  Google Scholar 

  6. The Lancet Public Health: Obesity prevention: changing perspectives. Lancet Public Health 8, e161 (2023). https://doi.org/10.1016/S2468-2667(23)00033-6

  7. A. Kohlgruber, L. Lynch, Adipose tissue inflammation in the pathogenesis of type 2 diabetes. Curr. Diab. Rep. 15, 92 (2015). https://doi.org/10.1007/s11892-015-0670-x

    Article  CAS  PubMed  Google Scholar 

  8. A. Sakers, M.K. De Siqueira, P. Seale, C.J. Villanueva, Adipose-tissue plasticity in health and disease. Cell 185, 419–446 (2022). https://doi.org/10.1016/j.cell.2021.12.016

    Article  CAS  PubMed  Google Scholar 

  9. L. Ranvier, Du dévelopment et de l’accroissement desvaiseaux sanguins. Arch. Physiol. Norm. Pathol. 6, 429–446 (1874)

    Google Scholar 

  10. C. Bénézech, N.-T. Luu, J.A. Walker, A.A. Kruglov, Y. Loo, K. Nakamura, Y. Zhang, S. Nayar, L.H. Jones, A. Flores-Langarica, A. McIntosh, J. Marshall, F. Barone, G. Besra, K. Miles, J.E. Allen, M. Gray, G. Kollias, A.F. Cunningham, D.R. Withers, K.M. Toellner, N.D. Jones, M. Veldhoen, S.A. Nedospasov, A.N.J. McKenzie, J.H. Caamaño, Inflammation-induced formation of fat-associated lymphoid clusters. Nat. Immunol. 16, 819–828 (2015). https://doi.org/10.1038/ni.3215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. J. Rangel-Moreno, J.E. Moyron-Quiroz, D.M. Carragher, K. Kusser, L. Hartson, A. Moquin, T.D. Randall, Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30, 731–743 (2009). https://doi.org/10.1016/j.immuni.2009.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. C.N. Lumeng, Innate immune activation in obesity. Mol. Asp. Med. 34, 12–29 (2013). https://doi.org/10.1016/j.mam.2012.10.002

    Article  CAS  Google Scholar 

  13. N. Esser, S. Legrand-Poels, J. Piette, A.J. Scheen, N. Paquot, Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract. 105, 141–150 (2014). https://doi.org/10.1016/j.diabres.2014.04.006

    Article  CAS  PubMed  Google Scholar 

  14. C.N. Lumeng, J.L. Bodzin, A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007). https://doi.org/10.1172/JCI29881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. C. Bogdan, Nitric oxide and the immune response. Nat. Immunol. 2, 907–916 (2001). https://doi.org/10.1038/ni1001-907

    Article  CAS  PubMed  Google Scholar 

  16. H.-J. Kim, T. Higashimori, S.-Y. Park, H. Choi, J. Dong, Y.-J. Kim, H.-L. Noh, Y.-R. Cho, G. Cline, Y.-B. Kim, J.K. Kim, Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53, 1060–1067 (2004). https://doi.org/10.2337/diabetes.53.4.1060

    Article  CAS  PubMed  Google Scholar 

  17. M. Blüher, M. Fasshauer, A. Tönjes, J. Kratzsch, M.R. Schön, R. Paschke, Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism. Exp. Clin. Endocrinol. Diabetes 113, 534–537 (2005). https://doi.org/10.1055/s-2005-872851

    Article  CAS  PubMed  Google Scholar 

  18. K.D. Nguyen, Y. Qiu, X. Cui, Y.P.S. Goh, J. Mwangi, T. David, L. Mukundan, F. Brombacher, R.M. Locksley, A. Chawla, Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011). https://doi.org/10.1038/nature10653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. D. Wu, A.B. Molofsky, H.-E. Liang, R.R. Ricardo-Gonzalez, H.A. Jouihan, J.K. Bando, A. Chawla, R.M. Locksley, Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011). https://doi.org/10.1126/science.1201475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Y. Qiu, K.D. Nguyen, J.I. Odegaard, X. Cui, X. Tian, R.M. Locksley, R.D. Palmiter, A. Chawla, Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014). https://doi.org/10.1016/j.cell.2014.03.066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. A.J. Knights, E.J. Vohralik, P.J. Houweling, E.S. Stout, L.J. Norton, S.J. Alexopoulos, J.J. Yik, H. Mat Jusoh, E.M. Olzomer, K.S. Bell-Anderson, K.N. North, K.L. Hoehn, M. Crossley, K.G.R. Quinlan, Eosinophil function in adipose tissue is regulated by Krüppel-like factor 3 (KLF3). Nat. Commun. 11, 2922 (2020). https://doi.org/10.1038/s41467-020-16758-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. W.R. Bolus, K.R. Peterson, M.J. Hubler, A.J. Kennedy, M.L. Gruen, A.H. Hasty, Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments. Mol. Metab. 8, 86–95 (2018). https://doi.org/10.1016/j.molmet.2017.12.004

    Article  CAS  PubMed  Google Scholar 

  23. H. Sunadome, H. Matsumoto, Y. Izuhara, T. Nagasaki, Y. Kanemitsu, Y. Ishiyama, C. Morimoto, T. Oguma, I. Ito, K. Murase, S. Muro, T. Kawaguchi, Y. Tabara, K. Chin, F. Matsuda, T. Hirai, Correlation between eosinophil count, its genetic background and body mass index: The Nagahama Study. Allergol. Int. 69, 46–52 (2020). https://doi.org/10.1016/j.alit.2019.05.012

    Article  CAS  PubMed  Google Scholar 

  24. K. Moussa, P. Gurung, B. Adams-Huet, S. Devaraj, I. Jialal, Increased eosinophils in adipose tissue of metabolic syndrome. J. Diabetes Complications 33, 535–538 (2019). https://doi.org/10.1016/j.jdiacomp.2019.05.010

    Article  PubMed  Google Scholar 

  25. A.B. Molofsky, J.C. Nussbaum, H.-E. Liang, S.J. Van Dyken, L.E. Cheng, A. Mohapatra, A. Chawla, R.M. Locksley, Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549 (2013). https://doi.org/10.1084/jem.20121964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. J.R. Brestoff, B.S. Kim, S.A. Saenz, R.R. Stine, L.A. Monticelli, G.F. Sonnenberg, J.J. Thome, D.L. Farber, K. Lutfy, P. Seale, D. Artis, Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015). https://doi.org/10.1038/nature14115

    Article  CAS  PubMed  Google Scholar 

  27. A.M. Miller, D.L. Asquith, A.J. Hueber, L.A. Anderson, W.M. Holmes, A.N. McKenzie, D. Xu, N. Sattar, I.B. McInnes, F.Y. Liew, Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ. Res. 107, 650–658 (2010). https://doi.org/10.1161/CIRCRESAHA.110.218867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. L. Lynch, M. Nowak, B. Varghese, J. Clark, A.E. Hogan, V. Toxavidis, S.P. Balk, D. O’Shea, C. O’Farrelly, M.A. Exley, Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37, 574–587 (2012). https://doi.org/10.1016/j.immuni.2012.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. L. Lynch, D. O’Shea, D.C. Winter, J. Geoghegan, D.G. Doherty, C. O’Farrelly, Invariant NKT cells and CD1d(+) cells amass in human omentum and are depleted in patients with cancer and obesity. Eur. J. Immunol. 39, 1893–1901 (2009). https://doi.org/10.1002/eji.200939349

    Article  CAS  PubMed  Google Scholar 

  30. L. Lynch, X. Michelet, S. Zhang, P.J. Brennan, A. Moseman, C. Lester, G. Besra, E.E. Vomhof-Dekrey, M. Tighe, H.-F. Koay, D.I. Godfrey, E.A. Leadbetter, D.B. Sant’Angelo, U. von Andrian, M.B. Brenner, Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nat. Immunol. 16, 85–95 (2015). https://doi.org/10.1038/ni.3047

    Article  CAS  PubMed  Google Scholar 

  31. L. Lynch, Adipose invariant natural killer T cells. Immunology 142, 337–346 (2014). https://doi.org/10.1111/imm.12269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. L. Lynch, A.E. Hogan, D. Duquette, C. Lester, A. Banks, K. LeClair, D.E. Cohen, A. Ghosh, B. Lu, M. Corrigan, D. Stevanovic, E. Maratos-Flier, D.J. Drucker, D. O’Shea, M. Brenner, iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24, 510–519 (2016). https://doi.org/10.1016/j.cmet.2016.08.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. M. Brigl, M.B. Brenner, CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004). https://doi.org/10.1146/annurev.immunol.22.012703.104608

    Article  CAS  PubMed  Google Scholar 

  34. A.C. Kohlgruber, S.T. Gal-Oz, N.M. LaMarche, M. Shimazaki, D. Duquette, H.-F. Koay, H.N. Nguyen, A.I. Mina, T. Paras, A. Tavakkoli, U. von Andrian, A.P. Uldrich, D.I. Godfrey, A.S. Banks, T. Shay, M.B. Brenner, L. Lynch, γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis. Nat. Immunol. 19, 464–474 (2018). https://doi.org/10.1038/s41590-018-0094-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. T. Mahlakõiv, A.-L. Flamar, L.K. Johnston, S. Moriyama, G.G. Putzel, P.J. Bryce, D. Artis, Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33. Sci. Immunol. 4, eaax0416 (2019). https://doi.org/10.1126/sciimmunol.aax0416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. M.-W. Lee, J.I. Odegaard, L. Mukundan, Y. Qiu, A.B. Molofsky, J.C. Nussbaum, K. Yun, R.M. Locksley, A. Chawla, Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87 (2015). https://doi.org/10.1016/j.cell.2014.12.011

    Article  CAS  PubMed  Google Scholar 

  37. D. Kolodin, N. van Panhuys, C. Li, A.M. Magnuson, D. Cipolletta, C.M. Miller, A. Wagers, R.N. Germain, C. Benoist, D. Mathis, Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab. 21, 543–557 (2015). https://doi.org/10.1016/j.cmet.2015.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. A. Vasanthakumar, K. Moro, A. Xin, Y. Liao, R. Gloury, S. Kawamoto, S. Fagarasan, L.A. Mielke, S. Afshar-Sterle, S.L. Masters, S. Nakae, H. Saito, J.M. Wentworth, P. Li, W. Liao, W.J. Leonard, G.K. Smyth, W. Shi, S.L. Nutt, S. Koyasu, A. Kallies, The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 16, 276–285 (2015). https://doi.org/10.1038/ni.3085

    Article  CAS  PubMed  Google Scholar 

  39. S. Winer, Y. Chan, G. Paltser, D. Truong, H. Tsui, J. Bahrami, R. Dorfman, Y. Wang, J. Zielenski, F. Mastronardi, Y. Maezawa, D.J. Drucker, E. Engleman, D. Winer, H.-M. Dosch, Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009). https://doi.org/10.1038/nm.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. M. Feuerer, L. Herrero, D. Cipolletta, A. Naaz, J. Wong, A. Nayer, J. Lee, A.B. Goldfine, C. Benoist, S. Shoelson, D. Mathis, Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009). https://doi.org/10.1038/nm.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. M.M. Tiemessen, A.L. Jagger, H.G. Evans, M.J.C. van Herwijnen, S. John, L.S. Taams, CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc. Natl Acad. Sci. USA 104, 19446–19451 (2007). https://doi.org/10.1073/pnas.0706832104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. D. Medrikova, T.P. Sijmonsma, K. Sowodniok, D.M. Richards, M. Delacher, C. Sticht, N. Gretz, T. Schafmeier, M. Feuerer, S. Herzig, Brown adipose tissue harbors a distinct sub-population of regulatory T cells. PloS One 10, e0118534 (2015). https://doi.org/10.1371/journal.pone.0118534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. T. Gnad, S. Scheibler, I. von Kügelgen, C. Scheele, A. Kilić, A. Glöde, L.S. Hoffmann, L. Reverte-Salisa, P. Horn, S. Mutlu, A. El-Tayeb, M. Kranz, W. Deuther-Conrad, P. Brust, M.E. Lidell, M.J. Betz, S. Enerbäck, J. Schrader, G.G. Yegutkin, C.E. Müller, A. Pfeifer, Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516, 395–399 (2014). https://doi.org/10.1038/nature13816

    Article  CAS  PubMed  Google Scholar 

  44. P.J. Schuler, Z. Saze, C.-S. Hong, L. Muller, D.G. Gillespie, D. Cheng, M. Harasymczuk, M. Mandapathil, S. Lang, E.K. Jackson, T.L. Whiteside, Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells. Clin. Exp. Immunol. 177, 531–543 (2014). https://doi.org/10.1111/cei.12354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. N. Baumgarth, The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat. Rev. Immunol. 11, 34–46 (2011). https://doi.org/10.1038/nri2901

    Article  CAS  PubMed  Google Scholar 

  46. L. Shen, M.H.Y. Chng, M.N. Alonso, R. Yuan, D.A. Winer, E.G. Engleman, B-1a lymphocytes attenuate insulin resistance. Diabetes 64, 593–603 (2015). https://doi.org/10.2337/db14-0554

    Article  CAS  PubMed  Google Scholar 

  47. S. Nishimura, I. Manabe, S. Takaki, M. Nagasaki, M. Otsu, H. Yamashita, J. Sugita, K. Yoshimura, K. Eto, I. Komuro, T. Kadowaki, R. Nagai, Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell Metab. 18, 759–766 (2013). https://doi.org/10.1016/j.cmet.2013.09.017

    Article  CAS  PubMed  Google Scholar 

  48. W.V. Trim, L. Lynch, Immune and non-immune functions of adipose tissue leukocytes. Nat. Rev. Immunol. 22, 371–386 (2022). https://doi.org/10.1038/s41577-021-00635-7

    Article  CAS  PubMed  Google Scholar 

  49. A. Hruby, F.B. Hu, The epidemiology of obesity: a big picture. PharmacoEconomics 33, 673–689 (2015). https://doi.org/10.1007/s40273-014-0243-x

    Article  PubMed  PubMed Central  Google Scholar 

  50. T. Kelly, W. Yang, C.-S. Chen, K. Reynolds, J. He, Global burden of obesity in 2005 and projections to 2030. Int. J. Obes. 2005 32, 1431–1437 (2008). https://doi.org/10.1038/ijo.2008.102

    Article  CAS  Google Scholar 

  51. S.M. Reilly, A.R. Saltiel, Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 13, 633–643 (2017). https://doi.org/10.1038/nrendo.2017.90

    Article  CAS  PubMed  Google Scholar 

  52. S.U. Amano, J.L. Cohen, P. Vangala, M. Tencerova, S.M. Nicoloro, J.C. Yawe, Y. Shen, M.P. Czech, M. Aouadi, Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 19, 162–171 (2014). https://doi.org/10.1016/j.cmet.2013.11.017

    Article  CAS  PubMed  Google Scholar 

  53. D.Y. Oh, H. Morinaga, S. Talukdar, E.J. Bae, J.M. Olefsky, Increased macrophage migration into adipose tissue in obese mice. Diabetes 61, 346–354 (2012). https://doi.org/10.2337/db11-0860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. H. Kanda, S. Tateya, Y. Tamori, K. Kotani, K. Hiasa, R. Kitazawa, S. Kitazawa, H. Miyachi, S. Maeda, K. Egashira, M. Kasuga, MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006). https://doi.org/10.1172/JCI26498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. S. Cinti, G. Mitchell, G. Barbatelli, I. Murano, E. Ceresi, E. Faloia, S. Wang, M. Fortier, A.S. Greenberg, M.S. Obin, Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005). https://doi.org/10.1194/jlr.M500294-JLR200

    Article  CAS  PubMed  Google Scholar 

  56. R.M. Pirzgalska, E. Seixas, J.S. Seidman, V.M. Link, N.M. Sánchez, I. Mahú, R. Mendes, V. Gres, N. Kubasova, I. Morris, B.A. Arús, C.M. Larabee, M. Vasques, F. Tortosa, A.L. Sousa, S. Anandan, E. Tranfield, M.K. Hahn, M. Iannacone, N.J. Spann, C.K. Glass, A.I. Domingos, Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017). https://doi.org/10.1038/nm.4422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. D.A. Jaitin, L. Adlung, C.A. Thaiss, A. Weiner, B. Li, H. Descamps, P. Lundgren, C. Bleriot, Z. Liu, A. Deczkowska, H. Keren-Shaul, E. David, N. Zmora, S.M. Eldar, N. Lubezky, O. Shibolet, D.A. Hill, M.A. Lazar, M. Colonna, F. Ginhoux, H. Shapiro, E. Elinav, I. Amit, Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 178, 686–698.e14 (2019). https://doi.org/10.1016/j.cell.2019.05.054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. N.C. Winn, E.M. Wolf, J.N. Garcia, A.H. Hasty, Exon 2-mediated deletion of Trem2 does not worsen metabolic function in diet-induced obese mice. J. Physiol. 600, 4485–4501 (2022). https://doi.org/10.1113/JP283684

    Article  CAS  PubMed  Google Scholar 

  59. D. Patsouris, P.-P. Li, D. Thapar, J. Chapman, J.M. Olefsky, J.G. Neels, Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8, 301–309 (2008). https://doi.org/10.1016/j.cmet.2008.08.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. K.T. Uysal, S.M. Wiesbrock, M.W. Marino, G.S. Hotamisligil, Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610–614 (1997). https://doi.org/10.1038/39335

    Article  CAS  PubMed  Google Scholar 

  61. J.M. Wentworth, G. Naselli, W.A. Brown, L. Doyle, B. Phipson, G.K. Smyth, M. Wabitsch, P.E. O’Brien, L.C. Harrison, Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59, 1648–1656 (2010). https://doi.org/10.2337/db09-0287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. L.H. Jackson-Jones, P. Smith, J.R. Portman, M.S. Magalhaes, K.J. Mylonas, M.M. Vermeren, M. Nixon, B.E.P. Henderson, R. Dobie, S. Vermeren, L. Denby, N.C. Henderson, D.J. Mole, C. Bénézech, Stromal cells covering omental fat-associated lymphoid clusters trigger formation of neutrophil aggregates to capture peritoneal contaminants. Immunity 52, 700–715.e6 (2020). https://doi.org/10.1016/j.immuni.2020.03.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. V. Elgazar-Carmon, A. Rudich, N. Hadad, R. Levy, Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J. Lipid Res. 49, 1894–1903 (2008). https://doi.org/10.1194/jlr.M800132-JLR200

    Article  CAS  PubMed  Google Scholar 

  64. Y. Watanabe, Y. Nagai, H. Honda, N. Okamoto, T. Yanagibashi, M. Ogasawara, S. Yamamoto, R. Imamura, I. Takasaki, H. Hara, M. Sasahara, M. Arita, S. Hida, S. Taniguchi, T. Suda, K. Takatsu, Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation. FASEB J. 33, 11821–11835 (2019). https://doi.org/10.1096/fj.201900477RR

    Article  CAS  PubMed  Google Scholar 

  65. J. Nijhuis, S.S. Rensen, Y. Slaats, F.M.H. van Dielen, W.A. Buurman, J.W.M. Greve, Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring) 17, 2014–2018 (2009). https://doi.org/10.1038/oby.2009.113

    Article  CAS  PubMed  Google Scholar 

  66. E. Brotfain, N. Hadad, Y. Shapira, E. Avinoah, A. Zlotnik, L. Raichel, R. Levy, Neutrophil functions in morbidly obese subjects. Clin. Exp. Immunol. 181, 156–163 (2015). https://doi.org/10.1111/cei.12631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. S. Talukdar, D.Y. Oh, G. Bandyopadhyay, D. Li, J. Xu, J. McNelis, M. Lu, P. Li, Q. Yan, Y. Zhu, J. Ofrecio, M. Lin, M.B. Brenner, J.M. Olefsky, Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012). https://doi.org/10.1038/nm.2885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. M.M. Altintas, A. Azad, B. Nayer, G. Contreras, J. Zaias, C. Faul, J. Reiser, A. Nayer, Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice. J. Lipid Res. 52, 480–488 (2011). https://doi.org/10.1194/jlr.M011338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. A. Divoux, S. Moutel, C. Poitou, D. Lacasa, N. Veyrie, A. Aissat, M. Arock, M. Guerre-Millo, K. Clément, Mast cells in human adipose tissue: link with morbid obesity, inflammatory status, and diabetes. J. Clin. Endocrinol. Metab. 97, E1677–E1685 (2012). https://doi.org/10.1210/jc.2012-1532

    Article  CAS  PubMed  Google Scholar 

  70. J. Liu, A. Divoux, J. Sun, J. Zhang, K. Clément, J.N. Glickman, G.K. Sukhova, P.J. Wolters, J. Du, C.Z. Gorgun, A. Doria, P. Libby, R.S. Blumberg, B.B. Kahn, G.S. Hotamisligil, G.-P. Shi, Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat. Med. 15, 940–945 (2009). https://doi.org/10.1038/nm.1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Y. Zhou, X. Yu, H. Chen, S. Sjöberg, J. Roux, L. Zhang, A.-H. Ivoulsou, F. Bensaid, C.-L. Liu, J. Liu, J. Tordjman, K. Clement, C.-H. Lee, G.S. Hotamisligil, P. Libby, G.-P. Shi, Leptin deficiency shifts mast cells toward anti-inflammatory actions and protects mice from obesity and diabetes by polarizing M2 macrophages. Cell Metab. 22, 1045–1058 (2015). https://doi.org/10.1016/j.cmet.2015.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. J. Wang, G.-P. Shi, Mast cell stabilization: novel medication for obesity and diabetes. Diabetes Metab. Res. Rev. 27, 919–924 (2011). https://doi.org/10.1002/dmrr.1272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. D.A. Gutierrez, S. Muralidhar, T.B. Feyerabend, S. Herzig, H.-R. Rodewald, Hematopoietic kit deficiency, rather than lack of mast cells, protects mice from obesity and insulin resistance. Cell Metab. 21, 678–691 (2015). https://doi.org/10.1016/j.cmet.2015.04.013

    Article  CAS  PubMed  Google Scholar 

  74. S. Nishimura, I. Manabe, M. Nagasaki, K. Eto, H. Yamashita, M. Ohsugi, M. Otsu, K. Hara, K. Ueki, S. Sugiura, K. Yoshimura, T. Kadowaki, R. Nagai, CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009). https://doi.org/10.1038/nm.1964

    Article  CAS  PubMed  Google Scholar 

  75. C. Duffaut, J. Galitzky, M. Lafontan, A. Bouloumié, Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem. Biophys. Res. Commun. 384, 482–485 (2009). https://doi.org/10.1016/j.bbrc.2009.05.002

    Article  CAS  PubMed  Google Scholar 

  76. U. Kintscher, M. Hartge, K. Hess, A. Foryst-Ludwig, M. Clemenz, M. Wabitsch, P. Fischer-Posovszky, T.F.E. Barth, D. Dragun, T. Skurk, H. Hauner, M. Blüher, T. Unger, A.-M. Wolf, U. Knippschild, V. Hombach, N. Marx, 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, 1304–1310 (2008). https://doi.org/10.1161/ATVBAHA.108.165100

    Article  CAS  PubMed  Google Scholar 

  77. K.J. Strissel, J. DeFuria, M.E. Shaul, G. Bennett, A.S. Greenberg, M.S. Obin, T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring) 18, 1918–1925 (2010). https://doi.org/10.1038/oby.2010.1

    Article  CAS  PubMed  Google Scholar 

  78. M. Moysidou, S. Karaliota, E. Kodela, M. Salagianni, Y. Koutmani, A. Katsouda, K. Kodella, P. Tsakanikas, S. Ourailidou, E. Andreakos, N. Kostomitsopoulos, D. Skokos, A. Chatzigeorgiou, K.-J. Chung, S. Bornstein, M.W. Sleeman, T. Chavakis, K.P. Karalis, CD8+ T cells in beige adipogenesis and energy homeostasis. JCI Insight 3, e95456 (2018). https://doi.org/10.1172/jci.insight.95456

    Article  PubMed  PubMed Central  Google Scholar 

  79. H. Yang, Y.-H. Youm, B. Vandanmagsar, A. Ravussin, J.M. Gimble, F. Greenway, J.M. Stephens, R.L. Mynatt, V.D. Dixit, Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J. Immunol. 185, 1836–1845 (2010). https://doi.org/10.4049/jimmunol.1000021

    Article  CAS  PubMed  Google Scholar 

  80. W.J. McDonnell, J.R. Koethe, S.A. Mallal, M.A. Pilkinton, A. Kirabo, M.K. Ameka, M.A. Cottam, A.H. Hasty, A.J. Kennedy, High CD8 T-cell receptor clonality and altered CDR3 properties are associated with elevated isolevuglandins in adipose tissue during diet-induced obesity. Diabetes 67, 2361–2376 (2018). https://doi.org/10.2337/db18-0040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. S. Tsai, X. Clemente-Casares, X.S. Revelo, S. Winer, D.A. Winer, Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases. Diabetes 64, 1886–1897 (2015). https://doi.org/10.2337/db14-1488

    Article  CAS  PubMed  Google Scholar 

  82. F.C. McGillicuddy, E.H. Chiquoine, C.C. Hinkle, R.J. Kim, R. Shah, H.M. Roche, E.M. Smyth, M.P. Reilly, Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J. Biol. Chem. 284, 31936–31944 (2009). https://doi.org/10.1074/jbc.M109.061655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. J. Park, J.Y. Huh, J. Oh, J.I. Kim, S.M. Han, K.C. Shin, Y.G. Jeon, S.S. Choe, J. Park, J.B. Kim, Activation of invariant natural killer T cells stimulates adipose tissue remodeling via adipocyte death and birth in obesity. Genes Dev. 33, 1657–1672 (2019). https://doi.org/10.1101/gad.329557.119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. K. Ohmura, N. Ishimori, Y. Ohmura, S. Tokuhara, A. Nozawa, S. Horii, Y. Andoh, S. Fujii, K. Iwabuchi, K. Onoé, H. Tsutsui, Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice. Arterioscler. Thromb. Vasc. Biol. 30, 193–199 (2010). https://doi.org/10.1161/ATVBAHA.109.198614

    Article  CAS  PubMed  Google Scholar 

  85. J.Y. Huh, Y.J. Park, J.B. Kim, Adipocyte CD1d determines adipose inflammation and insulin resistance in obesity. Adipocyte 7, 129–136 (2018). https://doi.org/10.1080/21623945.2018.1440928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. J.Y. Huh, J. Park, J.I. Kim, Y.J. Park, Y.K. Lee, J.B. Kim, Deletion of CD1d in adipocytes aggravates adipose tissue inflammation and insulin resistance in obesity. Diabetes 66, 835–847 (2017). https://doi.org/10.2337/db16-1122

    Article  CAS  PubMed  Google Scholar 

  87. P. Mehta, A.M. Nuotio-Antar, C.W. Smith, γδ T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. J. Leukoc. Biol. 97, 121–134 (2015). https://doi.org/10.1189/jlb.3A0414-211RR

    Article  CAS  PubMed  Google Scholar 

  88. J.M. Olefsky, C.K. Glass, Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010). https://doi.org/10.1146/annurev-physiol-021909-135846

    Article  CAS  PubMed  Google Scholar 

  89. M.S.H. Akash, K. Rehman, A. Liaqat, Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J. Cell. Biochem. 119, 105–110 (2018). https://doi.org/10.1002/jcb.26174

    Article  CAS  PubMed  Google Scholar 

  90. D.A. Winer, S. Winer, L. Shen, P.P. Wadia, J. Yantha, G. Paltser, H. Tsui, P. Wu, M.G. Davidson, M.N. Alonso, H.X. Leong, A. Glassford, M. Caimol, J.A. Kenkel, T.F. Tedder, T. McLaughlin, D.B. Miklos, H.-M. Dosch, E.G. Engleman, B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011). https://doi.org/10.1038/nm.2353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. A. Fleischman, S.E. Shoelson, R. Bernier, A.B. Goldfine, Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31, 289–294 (2008). https://doi.org/10.2337/dc07-1338

    Article  CAS  PubMed  Google Scholar 

  92. A.B. Goldfine, R. Silver, W. Aldhahi, D. Cai, E. Tatro, J. Lee, S.E. Shoelson, Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin. Transl. Sci. 1, 36–43 (2008). https://doi.org/10.1111/j.1752-8062.2008.00026.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. A.B. Goldfine, V. Fonseca, K.A. Jablonski, L. Pyle, M.A. Staten, S.E. Shoelson,TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team, The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med. 152, 346–357 (2010). https://doi.org/10.7326/0003-4819-152-6-201003160-00004

  94. E. Faghihimani, A. Aminorroaya, H. Rezvanian, P. Adibi, F. Ismail-Beigi, M. Amini, Reduction of insulin resistance and plasma glucose level by salsalate treatment in persons with prediabetes. Endocr. Pract. 18, 826–833 (2012). https://doi.org/10.4158/EP12064.OR

    Article  PubMed  Google Scholar 

  95. A.B. Goldfine, P.R. Conlin, F. Halperin, J. Koska, P. Permana, D. Schwenke, S.E. Shoelson, P.D. Reaven, A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia 56, 714–723 (2013). https://doi.org/10.1007/s00125-012-2819-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. S. Koppaka, S. Kehlenbrink, M. Carey, W. Li, E. Sanchez, D.-E. Lee, H. Lee, J. Chen, E. Carrasco, P. Kishore, K. Zhang, M. Hawkins, Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans. Diabetes 62, 1843–1854 (2013). https://doi.org/10.2337/db12-0868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. D.H. Solomon, E. Massarotti, R. Garg, J. Liu, C. Canning, S. Schneeweiss, Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA 305, 2525–2531 (2011). https://doi.org/10.1001/jama.2011.878

    Article  CAS  PubMed  Google Scholar 

  98. F. Ofei, S. Hurel, J. Newkirk, M. Sopwith, R. Taylor, Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45, 881–885 (1996). https://doi.org/10.2337/diab.45.7.881

    Article  PubMed  Google Scholar 

  99. J.H. Huh, H.M. Kim, E.S. Lee, M.H. Kwon, B.R. Lee, H.-J. Ko, C.H. Chung, Dual CCR2/5 antagonist attenuates obesity-induced insulin resistance by regulating macrophage recruitment and M1/M2 status. Obesity (Silver Spring) 26, 378–386 (2018). https://doi.org/10.1002/oby.22103

    Article  CAS  PubMed  Google Scholar 

  100. N.A. Di Prospero, E. Artis, P. Andrade-Gordon, D.L. Johnson, N. Vaccaro, L. Xi, P. Rothenberg, CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Diabetes Obes. Metab. 16, 1055–1064 (2014). https://doi.org/10.1111/dom.12309

    Article  CAS  PubMed  Google Scholar 

  101. S.K. Biswas, Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435–449 (2015). https://doi.org/10.1016/j.immuni.2015.09.001

    Article  CAS  PubMed  Google Scholar 

  102. C. Jing, T. Castro-Dopico, N. Richoz, Z.K. Tuong, J.R. Ferdinand, L.S.C. Lok, K.W. Loudon, G.D. Banham, R.J. Mathews, Z. Cader, S. Fitzpatrick, K.R. Bashant, M.J. Kaplan, A. Kaser, R.S. Johnson, M.P. Murphy, R.M. Siegel, M.R. Clatworthy, Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis. Proc. Natl Acad. Sci. USA 117, 15160–15171 (2020). https://doi.org/10.1073/pnas.2000943117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. P. García-González, G. Ubilla-Olguín, D. Catalán, K. Schinnerling, J.C. Aguillón, Tolerogenic dendritic cells for reprogramming of lymphocyte responses in autoimmune diseases. Autoimmun. Rev. 15, 1071–1080 (2016). https://doi.org/10.1016/j.autrev.2016.07.032

    Article  PubMed  Google Scholar 

  104. A.D. Hildreth, F. Ma, Y.Y. Wong, R. Sun, M. Pellegrini, T.E. O’Sullivan, Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Nat. Immunol. 22, 639–653 (2021). https://doi.org/10.1038/s41590-021-00922-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. I. Magalhaes, K. Pingris, C. Poitou, S. Bessoles, N. Venteclef, B. Kiaf, L. Beaudoin, J. Da Silva, O. Allatif, J. Rossjohn, L. Kjer-Nielsen, J. McCluskey, S. Ledoux, L. Genser, A. Torcivia, C. Soudais, O. Lantz, C. Boitard, J. Aron-Wisnewsky, E. Larger, K. Clément, A. Lehuen, Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J. Clin. Invest. 125, 1752–1762 (2015). https://doi.org/10.1172/JCI78941

    Article  PubMed  PubMed Central  Google Scholar 

  106. C.E. Macdougall, E.G. Wood, J. Loschko, V. Scagliotti, F.C. Cassidy, M.E. Robinson, N. Feldhahn, L. Castellano, M.-B. Voisin, F. Marelli-Berg, C. Gaston-Massuet, M. Charalambous, M.P. Longhi, Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab. 27, 588–601.e4 (2018). https://doi.org/10.1016/j.cmet.2018.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-2-002); the National Natural Science Foundation of China (No.82270913); the Beijing Natural Science Foundation (No.7222137); the National Key Clinical Specialty Capacity Improvement Project; the National Key Program of Clinical Science (WBYZ2011-873) and the PUMCH Foundation (pumch-2013-020).

Author information

Authors and Affiliations

  1. Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, 100730, China

    Yuchen Jiang & Fengying Gong

Authors
  1. Yuchen Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fengying Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.J. performed the literature search and data analysis, and drafted the primary manuscript. F.G. designed and supervised the project, and critically revised the primary manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Fengying Gong.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, Y., Gong, F. Immune cells in adipose tissue microenvironment under physiological and obese conditions. Endocrine 83, 10–25 (2024). https://doi.org/10.1007/s12020-023-03521-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-023-03521-5

Keywords

Search

Navigation