Adipose tissue NK cells and inflammation and insulin resistance in obesity

描述(申请人提供)：肥胖与全身炎症状态有关，这是糖尿病和代谢综合征发病机制的基础，其起源于脂肪组织。脂肪组织炎症的细胞和分子机制还不是很清楚。虽然脂肪组织巨噬细胞(ATM)是炎症和全身性胰岛素抵抗的中心介质，但其他白细胞也发挥了作用。NK细胞在其他疾病状态下调节巨噬细胞的功能，但此前很少有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是一种未被充分研究的细胞类型，是ATM介导的脂肪组织炎症的重要上游调节因子，因此是调控ATM功能以改善肥胖相关炎症和胰岛素抵抗的极佳研究靶点。我们的初步数据显示，ATNK在肥胖中增加，ATNK衍生的干扰素在促进ATM炎症反应中发挥作用。我们的长期目标是开发基于ATNK的代谢性疾病的新型免疫疗法。这项建议的目标是：确定在人类肥胖中频率增加的可能的致病ATNK亚群，驱动它们激活的细胞因子刺激，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(目标I，II)，并确定体内去除NK细胞对肥胖小鼠全身炎症和胰岛素抵抗的影响(目标III)。我们的中心假设是，特定的ATNK亚群在人类肥胖中出现的频率增加，并推动ATM炎症反应和胰岛素抵抗，体内切除NK细胞将减轻小鼠肥胖的全身炎症和胰岛素抵抗。这项工作的基本原理是，识别致病的ATNK亚群和调节其功能的上游细胞因子刺激将为未来针对这些介质的体内免疫中和作用的研究提供靶点，以此作为减轻胰岛素抵抗和代谢性疾病的手段。 公共卫生相关性：脂肪组织炎症是许多肥胖相关疾病的基础，阐明其机制将指导针对肥胖相关代谢性疾病开发治疗方法的研究。NK细胞是脂肪组织炎症的细胞介质，目前尚未得到充分研究。这项建议将研究NK细胞在人类脂肪组织炎症中的作用，以及体内系统性NK细胞在小鼠肥胖中的作用，作为开发基于NK细胞的代谢性疾病治疗的第一步。

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. PUBLIC HEALTH RELEVANCE: Adipose tissue inflammation underlies numerous obesity-related diseases and elucidation of its mechanisms will guide research directed towards developing therapy for obesity-related metabolic disease. NK cells are understudied cellular mediators of adipose tissue inflammation. This proposal will study the role of NK cells in human adipose tissue inflammation and the efficacy of in vivo systemic NK cell knockdown in murine obesity as first steps towards developing NK cell-based therapy for metabolic disease.