Glycolipid-Reactive NKT Cells, Obesity and Insulin Resistance

描述（由申请人提供）：近几十年来，肥胖症的发病率急剧增加。因此，肥胖及其合并症，最显著的是胰岛素抵抗和2型糖尿病（T2 D），对全球健康构成严重威胁。特别令人关切的是，儿童肥胖症日益流行，儿童中与肥胖有关的代谢紊乱增加。现在清楚的是，肥胖伴随着低度全身性炎症，并且这种慢性炎症状态加剧了脂质积聚，并有助于肥胖相关合并症的发展。尽管我们在了解肥胖相关异常以及慢性炎症如何促成其合并症方面取得了这些进展，但关于引发和促进肥胖中慢性炎症的因素和分子事件仍有许多有待了解。在PI实验室中使用肥胖小鼠模型进行的初步研究提供了强有力的证据，表明1）不同的饮食脂质对称为自然杀伤T（NKT）细胞的免疫细胞亚群的功能活性有不同的影响，这些细胞对脂质起反应，并在调节免疫和炎症反应中发挥关键作用; 2）高脂饮食（HFD）使NKT细胞倾向于促炎表型细胞因子产生谱; 3）NKT细胞缺乏部分地防止HFD诱导的体重增加、脂肪肝和胰岛素抵抗; 4）NKT细胞缺乏改善组织中的炎症状态和巨噬细胞含量;和5）NKT细胞特异性激动剂-半乳糖神经酰胺对NKT细胞的慢性刺激加剧HFD诱导的脂肪肝和胰岛素抵抗。这些发现表明，肥胖症中脂质升高导致NKT细胞功能障碍，这反过来又在肥胖相关代谢疾病中起致病作用。因此，NKT细胞代表了在肥胖期间中断代谢紊乱和炎症之间的恶性循环的有吸引力的靶点。该项目将测试NKT细胞通过与抗原呈递细胞相互作用对脂质变化做出反应，从而促进慢性炎症的发展，从而加剧肥胖及其代谢后果，特别是胰岛素抵抗和T2 D。我们提出了4个综合目的：目的1：研究肥胖症中脂质过量调节NKT细胞功能的细胞和分子机制;目的2：确定NKT细胞功能障碍在引发和/或加重肥胖症中慢性炎症、巨噬细胞极化和全身胰岛素抵抗中的作用;目的3：评估不同NKT细胞特异性外源激动剂对肥胖引发的炎症和胰岛素抵抗的影响;目的4：评估肥胖儿童NKT细胞的功能活性。完成本提案中描述的工作将为基础NKT细胞生物学和肥胖引发的炎症的发展提供新的见解，并将为开发安全有效的基于NKT细胞的预防措施和治疗提供强有力的理由，以纠正过度肥胖及其代谢后果，特别是T2 D。第1页

DESCRIPTION (provided by applicant): The incidence of obesity has increased dramatically during recent decades. Consequently, obesity and its comorbidities, most notably insulin resistance and Type 2 diabetes (T2D), constitute a serious threat to global health. Of particular concern is the growing epidemic of childhood obesity and the increases in obesity-related metabolic disorders in children. It is now clear that obesity is accompanied by a low-grade systemic inflammation, and that this chronic inflammatory state exacerbates lipid accumulation and contributes to the development of obesity-associated comorbidities. Despite these advances in our understanding of obesity- associated abnormalities and how chronic inflammation contributes to its comorbidities, much remains to be learned regarding the factors and the molecular events that initiate and promote chronic inflammation in obesity. Preliminary studies performed in the PIs' laboratories, using mouse models of obesity, have provided strong evidence indicating that 1) distinct dietary lipids differentially influence the functional activity of a subset of immune cells called Natural Killer T (NKT) cells, which react to lipids and play a critical role in regulating immune and inflammatory responses; 2) a high fat diet (HFD) skews NKT cells towards a proinflammatory phenotype cytokine production profile; 3) NKT cell deficiency partially protects against HFD-induced weight gain, fatty liver, and insulin resistance; 4) NKT cell deficiency ameliorates inflammatory status and macrophage content in tissues; and 5) chronic stimulation of NKT cells by the NKT cell specific agonist - galactosylceramide exacerbates HFD-induced fatty liver and insulin resistance. These findings suggest a scenario in which elevated lipids in obesity cause NKT cell dysfunction, which in turn plays a pathogenic role in obesity-related metabolic diseases. As such, NKT cells represent attractive targets for interrupting the vicious cycle between metabolic disorders and inflammation during obesity. The proposed project will test the hypothesis that NKT cells, by responding to changes in lipids through interactions with antigen-presenting cells, contribute to the development of chronic inflammation, thereby exacerbating obesity and its metabolic consequences, in particular insulin resistance and T2D. We propose 4 integrated Aims: Aim 1: To investigate the cellular and molecular mechanisms by which lipid excess modulates NKT cell function in obesity; Aim 2: To determine the role of NKT cell dysfunction in initiating and/or exacerbating chronic inflammation, macrophage polarization, and systemic insulin resistance in obesity; Aim 3: To evaluate the impact of distinct NKT cell specific exogenous agonists on obesity-triggered inflammation and insulin resistance; and Aim 4: To assess the functional activity of NKT cells in obese children. Completion of the work described in this proposal will provide novel insight into fundamental NKT cell biology and the development of obesity-triggered inflammation, and will provide a strong rationale for developing safe and effective NKT cell-based preventive measures and therapies for correcting excess adiposity and its metabolic consequences, in particular T2D. Page 1