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:

Bariatric Surgery

IFNγ-producing NK cells in adipose tissue are associated with hyperglycemia and insulin resistance in obese women

International Journal of Obesity volume 45, pages 1607–1617 (2021)Cite this article

Subjects

Abstract

Background/objectives

Innate lymphoid cells (ILCs) play an important role in the maintenance of immune and metabolic homeostasis in adipose tissue (AT). The crosstalk between AT ILCs and adipocytes and other immune cells coordinates adipocyte differentiation, beiging, glucose metabolism and inflammation. Although the metabolic and homeostatic functions of mouse ILCs have been extensively investigated, little is known about human adipose ILCs and their roles in obesity and insulin resistance (IR).

Subjects/methods

Here we characterized T and NK cell populations in omental AT (OAT) from women (n = 18) with morbid obesity and varying levels of IR and performed an integrated analysis of metabolic parameters and adipose tissue transcriptomics.

Results

In OAT, we found a distinct population of CD56–NKp46+EOMES+ NK cells characterized by expression of cytotoxic molecules, pro-inflammatory cytokines, and markers of cell activation. AT IFNγ+ NK cells, but not CD4, CD8 or γδ T cells, were positively associated with glucose levels, glycated hemoglobin (HbA1c) and IR. AT NK cells were linked to a pro-inflammatory gene expression profile in AT and developed an effector phenotype in response to IL-12 and IL-15. Moreover, integrated transcriptomic analysis revealed a potential implication of AT IFNγ+ NK cells in controlling adipose tissue inflammation, remodeling, and lipid metabolism.

Conclusions

Our results suggest that a distinct IFNγ−producing NK cell subset is involved in metabolic homeostasis in visceral AT in humans with obesity and may be a potential target for therapy of IR.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: IFNγ-expressing lymphoid cells in human OAT.
Fig. 2: Characteristics of AT and blood ILCs.
Fig. 3: AT NK cells are associated with local and systemic inflammation.
Fig. 4: AT IFNγ+ NK cells are associated with perturbed glucose control.
Fig. 5: Integrated analysis of gene expression in OAT and immune and metabolic parameters.

Similar content being viewed by others

References

  1. Heymsfield SB, Wadden TA. Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med. 2017;376:254–66.

    Article  CAS  PubMed  Google Scholar 

  2. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1545–602.

    Article  Google Scholar 

  3. Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542:177–85.

    Article  CAS  PubMed  Google Scholar 

  4. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11:98–107.

    Article  CAS  PubMed  Google Scholar 

  5. Brestoff JR, Artis D. Immune regulation of metabolic homeostasis in health and disease. Cell. 2015;161:146–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity. 2018;48:1104–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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;519:242–6.

    Article  CAS  PubMed  Google Scholar 

  8. Liu M, Zhang C. The Role of Innate Lymphoid Cells in Immune-Mediated Liver Diseases. Front Immunol. 2017;8:695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate Lymphoid Cells: 10 Years On. Cell. 2018;174:1054–66.

    Article  CAS  PubMed  Google Scholar 

  10. Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015;517:293–301.

    Article  CAS  PubMed  Google Scholar 

  11. Boulenouar S, Michelet X, Duquette D, Alvarez D, Hogan AE, Dold C, et al. Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity. Cell Metab. 2017;46:273–86.

    CAS  Google Scholar 

  12. 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;16:376–85.

    Article  CAS  PubMed  Google Scholar 

  13. 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;23:685–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Strissel KJ, DeFuria J, Shaul ME, Bennett G, Greenberg AS, Obin MS. T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring). 2010;18:1918–25.

    Article  CAS  Google Scholar 

  15. Rocha VZ, Folco EJ, Sukhova G, Shimizu K, Gotsman I, Vernon AH, et al. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res. 2008;103:467–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wentworth JM, Zhang JG, Bandala-Sanchez E, Naselli G, Liu R, Ritchie M, et al. Interferon-gamma released from omental adipose tissue of insulin-resistant humans alters adipocyte phenotype and impairs response to insulin and adiponectin release. Int J Obes (Lond). 2017;41:1782–9.

    Article  CAS  Google Scholar 

  17. Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care. 1998;21:2191–2.

    Article  CAS  PubMed  Google Scholar 

  18. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–70.

    Article  CAS  PubMed  Google Scholar 

  19. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4:249–64.

    Article  PubMed  Google Scholar 

  20. Gautier L, Cope L, Bolstad BM, Irizarry RA. affy−analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–15.

    Article  CAS  PubMed  Google Scholar 

  21. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinform. 2008;9:559.

    Article  Google Scholar 

  22. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kallies A, Good-Jacobson KL. Transcription Factor T-bet Orchestrates Lineage Development and Function in the Immune System. Trends Immunol. 2017;38:287–97.

    Article  CAS  PubMed  Google Scholar 

  24. Morris DL, Cho KW, Delproposto JL, Oatmen KE, Geletka LM, Martinez-Santibanez G, et al. Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes. 2013;62:2762–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cho KW, Morris DL, DelProposto JL, Geletka L, Zamarron B, Martinez-Santibanez G, et al. An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. Cell Rep. 2014;9:605–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15:914–20.

    Article  CAS  PubMed  Google Scholar 

  27. McLaughlin T, Liu LF, Lamendola C, Shen L, Morton J, Rivas H, et al. T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol. 2014;34:2637–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Eberl G, Colonna M, Di Santo JP, McKenzie AN. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science. 2015;348:aaa6566.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Klose CSN, Flach M, Mohle L, Rogell L, Hoyler T, Ebert K, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014;157:340–56.

    Article  CAS  PubMed  Google Scholar 

  30. Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, Strowig T, et al. Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci U S A. 2004;101:16606–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156:20–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875–80.

    Article  PubMed  Google Scholar 

  33. Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Investig. 2011;121:2094–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov. 2016;15:639–60.

    Article  CAS  PubMed  Google Scholar 

  35. Mathis D. Immunological goings-on in visceral adipose tissue. Cell Metab. 2013;17:851–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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;45:428–41.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Simoni Y, Fehlings M, Kloverpris HN, McGovern N, Koo SL, Loh CY, et al. Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency. Immunity. 2017;46:148–61.

    Article  CAS  PubMed  Google Scholar 

  38. Yudanin NA, Schmitz F, Flamar AL, Thome JJC, Tait Wojno E, Moeller JB, et al. Spatial and Temporal Mapping of Human Innate Lymphoid Cells Reveals Elements of Tissue Specificity. Immunity. 2019;50:505–19 e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gauthier MS, Ruderman NB. Adipose tissue inflammation and insulin resistance: all obese humans are not created equal. Biochem J. 2010;430:e1–4.

    Article  CAS  PubMed  Google Scholar 

  40. Lawler HM, Underkofler CM, Kern PA, Erickson C, Bredbeck B, Rasouli N. Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects. J Clin Endocrinol Metab. 2016;101:1422–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Frank AP, de Souza Santos R, Palmer BF, Clegg DJ. Determinants of body fat distribution in humans may provide insight about obesity-related health risks. J Lipid Res. 2019;60:1710–9.

    Article  CAS  PubMed  Google Scholar 

  42. Despres JP, Lemieux I, Prud’homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ. 2001;322:716–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Hélène Dehondt and Céline Gheeraert (Inserm U1011) for help with the microarray assay and members of BioImaging Center Lille-Nord of France (BICeL) for assistance with flow cytometry.

Funding

This work was supported by grants from the ANR and the European Union: EGID ANR-10-LABX-46. BS is a recipient of an Advanced European Research Council (ERC) grant (number 694717).

Author information

Author notes

  1. Denis A. Mogilenko

    Present address: Washington University School of Medicine, Department of Pathology & Immunology, Saint Louis, MO, USA

Authors and Affiliations

  1. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France

    Denis A. Mogilenko, Laurent L’homme, Laurent Pineau, Bruno Derudas, Bart Staels & David Dombrowicz

  2. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1190-EGID, Lille, France

    Robert Caiazzo, Violeta Raverdy, Jerome Noulette & Francois Pattou

Authors
  1. Denis A. Mogilenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Caiazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurent L’homme
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laurent Pineau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Violeta Raverdy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jerome Noulette
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bruno Derudas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francois Pattou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bart Staels
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David Dombrowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DAM, BS, FP, and DD conceived the study and designed the experiments. DAM, BS, and DD interpreted data and wrote the paper. RC, VR, and JN collected human biopsies. BD performed microarray assay. DAM, LP, and LL performed flow cytometry, DAM performed transcriptomic analysis and WGCNA.

Corresponding author

Correspondence to David Dombrowicz.

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.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mogilenko, D.A., Caiazzo, R., L’homme, L. et al. IFNγ-producing NK cells in adipose tissue are associated with hyperglycemia and insulin resistance in obese women. Int J Obes 45, 1607–1617 (2021). https://doi.org/10.1038/s41366-021-00826-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-021-00826-1

Search

Advanced search

Quick links