NK cells link obesity-induced adipose stress to inflammation and insulin resistance.
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.
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Felix M
FM
Wensveen
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Vedrana
V
Jelenčić
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Sonja
S
Valentić
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Marko
M
Šestan
Department of Internal Medicine, University Hospital Rijeka, Rijeka, Croatia.
Tamara Turk
TT
Wensveen
Max Planck Institute for Metabolism Research Cologne, Cologne, Germany.
Sebastian
S
Theurich
The Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
Ariella
A
Glasner
Department of Surgery, University Hospital Rijeka, Rijeka, Croatia.
Davor
D
Mendrila
Department of Internal Medicine, University Hospital Rijeka, Rijeka, Croatia.
Davor
D
Štimac
Max Planck Institute for Metabolism Research Cologne, Cologne, Germany.
F Thomas
FT
Wunderlich
Max Planck Institute for Metabolism Research Cologne, Cologne, Germany.
Jens C
JC
Brüning
The Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
Ofer
O
Mandelboim
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Bojan
0000000339309630
B
Polić
D017667:Adipocytes / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007328:Insulin / Q000276:immunology; D007333:Insulin Resistance / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D050152:Intra-Abdominal Fat / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000276:immunology; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction
D000950:Antigens, Ly; D007328:Insulin; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D007371:Interferon-gamma