1. IL-6/Stat3-Dependent Induction of a Distinct, Obesity-Associated NK Cell Subpopulation Deteriorates Energy and Glucose Homeostasis
- Author
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Jens C. Brüning, Adelheid Lempradl, Sebastian Theurich, Katharina Schilbach, John Andrew Pospisilik, Kat Folz-Donahue, F. Thomas Wunderlich, Ruth Hanssen, Katharina Timper, Veronika Sexl, Christian Heilinger, Jan Mauer, and Eva Tsaousidou
- Subjects
0301 basic medicine ,Adult ,Male ,STAT3 Transcription Factor ,Myeloid ,Physiology ,Population ,Mice, Obese ,Inflammation ,Biology ,03 medical and health sciences ,Interleukin 21 ,Mice ,Young Adult ,Insulin resistance ,medicine ,Glucose homeostasis ,Animals ,Homeostasis ,Humans ,Obesity ,Receptor ,education ,Molecular Biology ,education.field_of_study ,Interleukin-6 ,Cell Biology ,medicine.disease ,Receptors, Interleukin-6 ,Killer Cells, Natural ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Glucose ,Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ,Immunology ,Interleukin 12 ,medicine.symptom ,Insulin Resistance ,Energy Metabolism ,Signal Transduction - Abstract
Summary Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance. We demonstrate that in mice obesity promotes expansion of a distinct, interleukin-6 receptor (IL6R)a-expressing NK subpopulation, which also expresses a number of other myeloid lineage genes such as the colony-stimulating factor 1 receptor (Csf1r). Selective ablation of this Csf1r-expressing NK cell population prevents obesity and insulin resistance. Moreover, conditional inactivation of IL6Ra or Stat3 in NK cells limits obesity-associated formation of these myeloid signature NK cells, protecting from obesity, insulin resistance, and obesity-associated inflammation. Also in humans IL6Ra + NK cells increase in obesity and correlate with markers of systemic low-grade inflammation, and their gene expression profile overlaps with characteristic gene sets of NK cells in obese mice. Collectively, we demonstrate that obesity-associated inflammation and metabolic disturbances depend on interleukin-6/Stat3-dependent formation of a distinct NK population, which may provide a target for the treatment of obesity, metaflammation-associated pathologies, and diabetes.
- Published
- 2016