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.
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.
Cell Metab. 2017 Jul 5;26(1):171-184.e6. doi: 10.1016/j.cmet.2017.05.018.
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.
自然杀伤 (NK) 细胞有助于肥胖相关胰岛素抵抗的发展。我们证明，在肥胖小鼠中，白细胞介素 6 受体 (IL6R)a 表达的 NK 亚群会扩增，该亚群还表达许多其他髓系谱系基因，如集落刺激因子 1 受体 (Csf1r)。选择性清除这种表达 Csf1r 的 NK 细胞群可预防肥胖和胰岛素抵抗。此外，NK 细胞中 IL6Ra 或 Stat3 的条件性失活限制了与肥胖相关的这些髓样特征 NK 细胞的形成，从而防止肥胖、胰岛素抵抗和肥胖相关炎症。同样，在人类中，肥胖时 IL6Ra NK 细胞增加，并与全身低度炎症的标志物相关，其基因表达谱与肥胖小鼠中 NK 细胞的特征基因集重叠。总之，我们证明肥胖相关的炎症和代谢紊乱依赖于白细胞介素 6/Stat3 依赖性形成的独特 NK 群体，这可能为肥胖、代谢炎症相关疾病和糖尿病的治疗提供一个靶点。
