Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Obesity-associated T-cell and macrophage activation improve partly after a lifestyle intervention

This article has been updated

Abstract

Background

The relation between low-grade inflammation and metabolic dysfunction in obesity is not fully explored.

Objective

To evaluate immune parameters in the obese state and after a lifestyle intervention program.

Methods

Patients with obesity (n = 87) from an academic obesity clinic were compared with controls with regard to macrophage and T-cell activation (reflected by serum levels of soluble CD163 (sCD163) and soluble IL-2 receptor (sIL-2R), respectively), and an array of cytokines, chemokines, and growth factors. In addition, these parameters and regulatory T-cells (Treg), were studied in 27 patients who followed a 75-week lifestyle intervention (dietary advice, exercise, and psychoeducation).

Results

Mean sIL-2R and sCD163 levels were higher in patients than controls (sIL-2R:2884 ± 936 pg/ml vs. 2207 ± 813 pg/ml, p = 0.001; sCD163:1279 ± 580 pg/ml vs. 661 ± 271 pg/ml, p < 0.0001 respectively). Patients with metabolic syndrome (MetS) had higher sCD163 than those without (1467 ± 656 pg/ml vs. 1103 ± 438 pg/ml). Patients had higher IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-15, IL-17A, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, G-CSF, GM-CSF, FGF, IFN-γ, and TNF-α than controls, whereas VEGF-A, PDGF-BB, and eotaxin were lower. Upon intervention, sIL-2R decreased while peripheral Treg frequencies increased within the reference range (p = 0.042 and p = 0.005 respectively). The sIL-2R decrease correlated to a decrease in waist circumference (rho = 0.388, p = 0.045) and in trend to a decrease in MetS components (rho = 0.345, p = 0.078). The Treg increase was unrelated to weight loss or metabolic improvement. Mean sCD163 did not change significantly upon intervention, nor did the cytokines, chemokines, and growth factors (except IP-10/CXCL10).

Conclusion

In obesity, T-cell homeostasis improves after a lifestyle intervention. Immunologic alterations can occur independently of metabolic improvement.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2: Longitudinal analyses of immune parameters.

Similar content being viewed by others

Change history

  • 24 October 2020

    The original HTML version of this Article was updated shortly after publication to add the supplementary data (which was previously completely absent).

References

  1. Collaborators GBDO. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377:13–27. https://doi.org/10.1056/NEJMoa1614362.

  2. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–5.

    CAS  Google Scholar 

  3. Hotamisligil GS. Foundations of immunometabolism and implications for metabolic health and disease. Immunity. 2017;47:406–20.

    CAS  Google Scholar 

  4. Cinkajzlova A, Mraz M, Haluzik M. Lymphocytes and macrophages in adipose tissue in obesity: markers or makers of subclinical inflammation? Protoplasma. 2017;254:1219–32.

    CAS  Google Scholar 

  5. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Investig. 2007;117:175–84.

    CAS  Google Scholar 

  6. Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017;79:541–66.

    CAS  Google Scholar 

  7. Kane H, Lynch L. Innate immune control of adipose tissue homeostasis. Trends Immunol. 2019;40:857–72.

    CAS  Google Scholar 

  8. Tateya S, Kim F, Tamori Y. Recent advances in obesity-induced inflammation and insulin resistance. Front Endocrinol. 2013;4:93.

    Google Scholar 

  9. Schmidt FM, Weschenfelder J, Sander C, Minkwitz J, Thormann J, Chittka T, et al. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS ONE. 2015;10:e0121971.

    Google Scholar 

  10. Etzerodt A, Moestrup SK. CD163 and inflammation: biological, diagnostic, and therapeutic aspects. Antioxid Redox Signal. 2013;18:2352–63.

    CAS  Google Scholar 

  11. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, et al. Identification of the haemoglobin scavenger receptor. Nature. 2001;409:198–201.

    CAS  Google Scholar 

  12. Zhi Y, Gao P, Xin X, Li W, Ji L, Zhang L, et al. Clinical significance of sCD163 and its possible role in asthma (Review). Mol Med Rep. 2017;15:2931–9.

    CAS  Google Scholar 

  13. Cinkajzlova A, Lacinova Z, Klouckova J, Kavalkova P, Trachta P, Kosak M, et al. An alternatively activated macrophage marker CD163 in severely obese patients: the influence of very low-calorie diet and bariatric surgery. Physiol Res. 2017;66:641–52.

    CAS  Google Scholar 

  14. Fjeldborg K, Christiansen T, Bennetzen M, H JM, Pedersen SB, Richelsen B. The macrophage-specific serum marker, soluble CD163, is increased in obesity and reduced after dietary-induced weight loss. Obesity. 2013;21:2437–43.

    CAS  Google Scholar 

  15. Zanni MV, Burdo TH, Makimura H, Williams KC, Grinspoon SK. Relationship between monocyte/macrophage activation marker soluble CD163 and insulin resistance in obese and normal-weight subjects. Clin Endocrinol. 2012;77:385–90.

    CAS  Google Scholar 

  16. Kracmerova J, Rossmeislova L, Kovacova Z, Klimcakova E, Polak J, Tencerova M, et al. Soluble CD163 is associated with CD163 mRNA expression in adipose tissue and with insulin sensitivity in steady-state condition but not in response to calorie restriction. J Clin Endocrinol Metab. 2014;99:E528–35.

    CAS  Google Scholar 

  17. Carreras-Badosa G, Prats-Puig A, Diaz-Roldan F, Platero-Gutierrez E, Osiniri I, Riera-Perez E, et al. The macrophage activation product sCD163 is associated with a less favourable metabolic profile in prepubertal children. Pediatr Obes. 2016;11:543–50.

    CAS  Google Scholar 

  18. Sorensen LP, Parkner T, Sondergaard E, Bibby BM, Moller HJ, Nielsen S. Visceral obesity is associated with increased soluble CD163 concentration in men with type 2 diabetes mellitus. Endocr Connect. 2015;4:27–36.

    Google Scholar 

  19. Parkner T, Sorensen LP, Nielsen AR, Fischer CP, Bibby BM, Nielsen S, et al. Soluble CD163: a biomarker linking macrophages and insulin resistance. Diabetologia. 2012;55:1856–62.

    CAS  Google Scholar 

  20. Deichgraeber P, Witte DR, Moller HJ, Skriver MV, Richelsen B, Jorgensen ME, et al. Soluble CD163, adiponectin, C-reactive protein and progression of dysglycaemia in individuals at high risk of type 2 diabetes mellitus: the ADDITION-PRO cohort. Diabetologia. 2016;59:2467–76.

    CAS  Google Scholar 

  21. Moller HJ. Soluble CD163. Scand J Clin Lab Investig. 2012;72:1–13.

    CAS  Google Scholar 

  22. Wagner NM, Brandhorst G, Czepluch F, Lankeit M, Eberle C, Herzberg S, et al. Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk. Obesity. 2013;21:461–8.

    CAS  Google Scholar 

  23. Agabiti-Rosei C, Trapletti V, Piantoni S, Airo P, Tincani A, De Ciuceis C, et al. Decreased circulating T regulatory lymphocytes in obese patients undergoing bariatric surgery. PLoS ONE. 2018;13:e0197178.

    Google Scholar 

  24. Touch S, Clement K, Andre ST. Cell populations and functions are altered in human obesity and type 2 diabetes. Curr Diab Rep. 2017;17:81.

    Google Scholar 

  25. van der Weerd K, Dik WA, Schrijver B, Schweitzer DH, Langerak AW, Drexhage HA, et al. Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype. Diabetes. 2012;61:401–8.

    Google Scholar 

  26. Rubin LA, Nelson DL. The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med. 1990;113:619–27.

    CAS  Google Scholar 

  27. Karim AF, Eurelings LEM, Bansie RD, van Hagen PM, van Laar JAM, Dik WA. Soluble interleukin-2 receptor: a potential marker for monitoring disease activity in IgG4-related disease. Mediators Inflamm. 2018;2018:6103064.

    CAS  Google Scholar 

  28. Groen-Hakan F, Eurelings L, ten Berge JC, van Laar J, Ramakers CRB, Dik WA, et al. Diagnostic value of serum-soluble interleukin 2 receptor levels vs angiotensin-converting enzyme in patients with sarcoidosis-associated uveitis. JAMA Ophthalmol. 2017;135:1352–8.

    Google Scholar 

  29. Tournadre A, Dubost JJ, Soubrier M, Ruivard M, Souteyrand P, Schmidt J, et al. Soluble IL-2 receptor: a biomarker for assessing myositis activity. Dis Markers. 2014;2014:472624.

    Google Scholar 

  30. Witkowska AM. On the role of sIL-2R measurements in rheumatoid arthritis and cancers. Mediators Inflamm. 2005;2005:121–30.

    Google Scholar 

  31. Grutters JC, Fellrath JM, Mulder L, Janssen R, van den Bosch JM, van Velzen-Blad H. Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation. Chest. 2003;124:186–95.

    CAS  Google Scholar 

  32. Doganay S, Evereklioglu C, Er H, Turkoz Y, Sevinc A, Mehmet N, et al. Comparison of serum NO, TNF-alpha, IL-1beta, sIL-2R, IL-6 and IL-8 levels with grades of retinopathy in patients with diabetes mellitus. Eye. 2002;16:163–70.

    CAS  Google Scholar 

  33. Wadwa RP, Kinney GL, Ogden L, Snell-Bergeon JK, Maahs DM, Cornell E, et al. Soluble interleukin-2 receptor as a marker for progression of coronary artery calcification in type 1 diabetes. Int J Biochem Cell Biol. 2006;38:996–1003.

    CAS  Google Scholar 

  34. Hamdy NM. Relationship between pro-anti-inflammatory cytokines, T-cell activation and CA 125 in obese patients with heart failure. Med Sci Monit. 2011;17:CR174–9.

    Google Scholar 

  35. Mangge H, Schauenstein K, Stroedter L, Griesl A, Maerz W, Borkenstein M. Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis. Exp Clin Endocrinol Diabetes. 2004;112:378–82.

    CAS  Google Scholar 

  36. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes—2018. Diabetes Care. 2018;41(Suppl 1):S13–S27.

    Google Scholar 

  37. Gezondheidsraad. Richtlijnen Goede Voeding 2015. 2015. https://www.gezondheidsraad.nl/binaries/gezondheidsraad/documenten/adviezen/2015/11/04/richtlijnen-goede-voeding-2015/201524_Richtlijnen+goede+voeding+2015.pdf.

  38. Seddiki N, Santner-Nanan B, Tangye SG, Alexander SI, Solomon M, Lee S, et al. Persistence of naive CD45RA+ regulatory T cells in adult life. Blood. 2006;107:2830–8.

    CAS  Google Scholar 

  39. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–11.

    CAS  Google Scholar 

  40. Wolf RM, Jaffe AE, Steele KE, Schweitzer MA, Magnuson TH, Wolfe A. et al. Cytokine, chemokine and cytokine receptor changes are associated with metabolic improvements after bariatric surgery. J Clin Endocrinol Metab. 2019;104:947–56. https://doi.org/10.1210/jc.2018-02245.

    Article  Google Scholar 

  41. Mirhafez SR, Pasdar A, Avan A, Esmaily H, Moezzi A, Mohebati M, et al. Cytokine and growth factor profiling in patients with the metabolic syndrome. Br J Nutr. 2015;113:1911–9.

    CAS  Google Scholar 

  42. Eckel N, Li Y, Kuxhaus O, Stefan N, Hu FB, Schulze MB. Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses’ Health Study): 30 year follow-up from a prospective cohort study. Lancet Diabetes Endocrinol. 2018;6:714–24.

    Google Scholar 

  43. Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nat Immunol. 2018;19:665–73.

    CAS  Google Scholar 

  44. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes. 2005;54:92–9.

    CAS  Google Scholar 

  45. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971–9.

    CAS  Google Scholar 

  46. Bonelli M, Savitskaya A, von Dalwigk K, Steiner CW, Aletaha D, Smolen JS, et al. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). Int Immunol. 2008;20:861–8.

    CAS  Google Scholar 

  47. Gentili A, Zaibi MS, Alomar SY, De Vuono S, Ricci MA, Alaeddin A, et al. Circulating levels of the adipokines monocyte chemotactic protein-4 (MCP-4), macrophage inflammatory protein-1beta (MIP-1beta), and eotaxin-3 in severe obesity and following bariatric surgery. Horm Metab Res. 2016;48:847–53.

    CAS  Google Scholar 

  48. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280:E745–51.

    CAS  Google Scholar 

  49. Catalan V, Gomez-Ambrosi J, Ramirez B, Rotellar F, Pastor C, Silva C, et al. Proinflammatory cytokines in obesity: impact of type 2 diabetes mellitus and gastric bypass. Obes Surg. 2007;17:1464–74.

    Google Scholar 

  50. Zafar MI, Mills K, Ye X, Blakely B, Min J, Kong W, et al. Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis. Diabetol Metab Syndr. 2018;10:62.

    Google Scholar 

  51. Rivera P, Martos-Moreno GA, Barrios V, Suarez J, Pavon FJ, Chowen JA, et al. A novel approach to childhood obesity: circulating chemokines and growth factors as biomarkers of insulin resistance. Pediatr Obes. 2019;14:e12473.

    CAS  Google Scholar 

  52. Tisato V, Toffoli B, Monasta L, Bernardi S, Candido R, Zauli G, et al. Patients affected by metabolic syndrome show decreased levels of circulating platelet derived growth factor (PDGF)-BB. Clin Nutr. 2013;32:259–64.

    CAS  Google Scholar 

  53. Luster AD, Ravetch JV. Biochemical characterization of a gamma interferon-inducible cytokine (IP-10). J Exp Med. 1987;166:1084–97.

    CAS  Google Scholar 

  54. Bray GA, Kim KK, Wilding JPH, World Obesity F. Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obes Rev. 2017;18:715–23.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E. F. C. van Rossum.

Ethics declarations

Conflict of interest

EV, IZ, VW, PL, and WD have nothing to disclose. ER is supported by the Elisabeth Foundation and the Netherlands Organization of Scientific Research NWO, Grant/Award Number: 91716453.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van der Zalm, I.J.B., van der Valk, E.S., Wester, V.L. et al. Obesity-associated T-cell and macrophage activation improve partly after a lifestyle intervention. Int J Obes 44, 1838–1850 (2020). https://doi.org/10.1038/s41366-020-0615-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-020-0615-6

Search

Quick links