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Abstract

An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell–activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress.

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Acknowledgements

We thank S. Slavić-Stupac, M. Samsa and K. Miklić for technical assistance and D. Jurišić-Eržen and M. Zelić for help with study setup. Supported by the European Foundation for the Study of Diabetes (New Horizons Program), the Unity through Knowledge Fund (15/13 to B.P.), the University of Rijeka (13.06.1.1.03 to B.P.), the Netherlands Organization for Scientific Research (91614029 to F.M.W.) and the European Commission (PCIG14-GA-2013-630827 to F.M.W.).

Author information

Author notes

    • Vedrana Jelenčić
    • , Sonja Valentić
    •  & Marko Šestan

    These authors contributed equally to this work.

Affiliations

  1. Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.

    • Felix M Wensveen
    • , Vedrana Jelenčić
    • , Sonja Valentić
    • , Marko Šestan
    •  & Bojan Polić
  2. Department of Internal Medicine, University Hospital Rijeka, Rijeka, Croatia.

    • Tamara Turk Wensveen
    •  & Davor Štimac
  3. Max Planck Institute for Metabolism Research Cologne, Cologne, Germany.

    • Sebastian Theurich
    • , F Thomas Wunderlich
    •  & Jens C Brüning
  4. The Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.

    • Ariella Glasner
    •  & Ofer Mandelboim
  5. Department of Surgery, University Hospital Rijeka, Rijeka, Croatia.

    • Davor Mendrila

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Contributions

F.M.W. designed and carried out most of the experiments and analyzed data. V.J., S.V., M.Š., T.T.W. and V.S. performed and analyzed experiments. A.G. generated key research reagents. D.M. obtained informed consent from patients and obtained human samples. D.Š. supervised the setup of the clinical study. F.T.W. and J.C.B. coordinated the metabolic studies. O.M. helped design studies with NCRGFP mice. B.P. directed the research and wrote the paper with F.M.W., with input from all coauthors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bojan Polić.

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DOI

https://doi.org/10.1038/ni.3120

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