Adipose tissue NK cells and inflammaton and insulin resistance in obesity

描述（由申请人提供）：肥胖与全身炎症状态相关，全身炎症是糖尿病和代谢综合征发病机制的基础，并在脂肪组织中发生。脂肪组织炎症的细胞和分子机制还不清楚。虽然脂肪组织巨噬细胞（ATM）是炎症和全身胰岛素抵抗的中心介质，但其他白细胞也发挥作用。NK细胞在其他疾病状态下调节巨噬细胞功能，但很少有先前的数据研究肥胖背景下的脂肪组织NK细胞（ATNK）及其在调节ATM炎症反应中的作用。ATNK是一种未充分研究的细胞类型，并且是ATM介导的脂肪组织炎症的重要推定上游调节因子，因此是针对操纵ATM功能以改善肥胖相关炎症和胰岛素抵抗为目标的研究的极好靶标。我们的初步数据表明肥胖患者ATNK增加，ATNK衍生的IFN-γ在促进ATM炎症反应中的作用。我们的长期目标是开发新的基于ATNK的代谢性疾病免疫疗法。本提案的目标是：鉴定在人类肥胖症中频率增加的推定致病性ATNK亚群、驱动其活化的细胞因子刺激物以及它们在调节人类脂肪组织中的炎症和胰岛素抵抗中的作用（目的I、II），并确定NK细胞的体内消融对肥胖小鼠中的全身性炎症和胰岛素抵抗的影响（目的III）。我们的中心假设是，特定的ATNK亚群在人类肥胖症中的频率增加，并驱动ATM炎症反应和胰岛素抵抗，并且NK细胞的体内消融将减弱小鼠肥胖症中的全身炎症和胰岛素抵抗。这项工作的基本原理是，鉴定致病性ATNK亚群和上游细胞因子刺激，调节其功能，将为未来的研究提供目标，这些介质的体内免疫中和作为一种手段，以减轻胰岛素抵抗和代谢疾病。

DESCRIPTION (provided by applicant): Obesity is associated with a state of systemic inflammation that underlies the pathogenesis of diabetes and metabolic syndrome and has its genesis in adipose tissue. The cellular and molecular mechanisms underlying adipose tissue inflammation are not well understood. While adipose tissue macrophages (ATM) are central mediators of inflammation and systemic insulin resistance, other leukocytes also play a role. NK cells regulate macrophage function in other disease states, but few prior data study adipose tissue NK cells (ATNK) in the context of obesity and their role in regulating ATM inflammatory responses. ATNK are an understudied cell type and an important putative upstream regulator of ATM- mediated adipose tissue inflammation, and are thus an excellent target for research directed towards manipulating ATM function with the goal of ameliorating obesity-related inflammation and insulin resistance. Our preliminary data demonstrate increased ATNK in obesity and a role for ATNK-derived IFN-¿ in promoting ATM inflammatory responses. Our long-term goal is to develop novel ATNK-based immunotherapy for metabolic disease. The goals of this proposal are: to identify putative pathogenic ATNK subpopulations that are increased in frequency in human obesity, the cytokine stimuli that drive their activation, and their role in regulating inflammation and insulin resistance in human adipose tissue (Aims I, II), and to determine the effect of in vivo ablation of NK cells on systemic inflammation and insulin resistance in obese mice (Aim III). Our central hypotheses are that specific ATNK subpopulations are increased in frequency in human obesity and drive ATM inflammatory responses and insulin resistance, and that in vivo ablation of NK cells will attenuate systemic inflammation and insulin resistance in murine obesity. The rationale for this work is that identification of pathogenic ATNK subpopulations and upstream cytokine stimuli that regulate their function will provide targets for future research directed towards in vivo immunoneutralization of these mediators as a means to attenuate insulin resistance and metabolic disease.