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

Publication date: 5 July 2017
Source:Cell Metabolism, Volume 26, Issue 1
Author(s): Sebastian Theurich, Eva Tsaousidou, Ruth Hanssen, Adelheid M. Lempradl, Jan Mauer, Katharina Timper, Katharina Schilbach, Kat Folz-Donahue, Christian Heilinger, Veronika Sexl, John Andrew Pospisilik, F. Thomas Wunderlich, Jens C. Brüning
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.

Graphical abstract

Teaser

A complex network of immune cells mediates obesity-associated low-grade inflammation. Theurich et al. describe a distinct, myeloid gene-expressing NK cell subpopulation that arises in obesity. Inhibition or depletion of this specific NK cell subpopulation decreases inflammation and protects from obesity and insulin resistance.


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