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Cell Metab. 2017 Jul 5;26(1):171-184.e6. doi: 10.1016/j.cmet.2017.05.018.

IL-6/Stat3-Dependent Induction of a Distinct, Obesity-Associated NK Cell Subpopulation Deteriorates Energy and Glucose Homeostasis.

Author information

1
Max-Planck-Institute for Metabolism Research, Gleueler Straße 50, 50931 Cologne, Germany; Department I of Internal Medicine, University Hospital Cologne, 50924 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
2
Max-Planck-Institute for Metabolism Research, Gleueler Straße 50, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany.
3
Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
4
Max-Planck-Institute for Biology of Ageing, FACS & Imaging Core Facility, 50931 Cologne, Germany.
5
Institute for Pharmacology and Toxicology, University of Veterinary Medicine, Veterinärplatz 1, 1210 Vienna, Austria.
6
Max-Planck-Institute for Metabolism Research, Gleueler Straße 50, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany. Electronic address: bruening@sf.mpg.de.

Abstract

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.

KEYWORDS:

Csf1r; IL-6 receptor; IL6Ra; Stat3; diabetes; metaflammation; myeloid gene signature; natural killer cells; obesity; obesity-associated inflammation

PMID:
28683285
DOI:
10.1016/j.cmet.2017.05.018
[Indexed for MEDLINE]
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