Glycolipid-Reactive NKT Cells, Obesity and Insulin Resistance

描述(申请人提供)：近几十年来，肥胖症的发病率急剧增加。因此，肥胖及其并发症，尤其是胰岛素抵抗和2型糖尿病，构成了对全球健康的严重威胁。特别令人关切的是，儿童肥胖症的流行日益严重，与肥胖有关的代谢紊乱在儿童中的增加。现在清楚的是，肥胖伴随着低级别的全身炎症，这种慢性炎症状态会加剧脂质堆积，并有助于肥胖相关合并症的发展。尽管我们对肥胖相关的异常以及慢性炎症如何导致其共病有了这些进展，但关于启动和促进肥胖症慢性炎症的因素和分子事件仍有许多需要了解。PIs的实验室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)不同的饮食脂质对一种称为自然杀伤T细胞(Natural Killer T，NKT)的免疫细胞亚群的功能活性有不同的影响，NKT细胞对脂类起反应，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细胞偏向致炎表型细胞因子产生谱；3)NKT细胞缺陷部分保护了HFD诱导的体重增加、脂肪肝和胰岛素抵抗；4)NKT细胞缺陷改善了组织中的炎症状态和巨噬细胞含量；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了HFD诱导的脂肪肝和胰岛素抵抗。这些发现表明，肥胖中血脂升高会导致NKT细胞功能障碍，而NKT细胞功能障碍又会在肥胖相关的代谢性疾病中发挥致病作用。因此，NKT细胞是阻断肥胖期间代谢紊乱和炎症之间恶性循环的有吸引力的靶点。这项拟议的项目将检验一种假设，即NKT细胞通过与抗原提呈细胞相互作用来应对血脂的变化，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T2D。我们提出了4个综合目标：目的1：研究脂肪过剩调节肥胖中NKT细胞功能的细胞和分子机制；目标2：确定NKT细胞功能障碍在启动和/或加剧肥胖中慢性炎症、巨噬细胞极化和全身性胰岛素抵抗中的作用；目标3：评估不同的NKT细胞特异性外源性激动剂对肥胖引发的炎症和胰岛素抵抗的影响；以及目标4：评估肥胖儿童中NKT细胞的功能活性。这项建议中所描述的工作的完成将为基础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细胞的预防措施和疗法提供强有力的理论基础，以纠正过度肥胖及其代谢后果，特别是T2D。第1页 公共卫生相关性：肥胖及其相关的代谢紊乱，如2型糖尿病，构成了对全球健康的严重威胁。这项拨款申请中提出的研究将调查被称为自然杀伤T(Natural Killer T，NKT)细胞的亚群免疫细胞如何变得功能失调，进而影响肥胖症和2型糖尿病的发展。自然杀伤T细胞对脂质起反应，并在建立免疫和炎症反应中发挥关键作用。这些拟议研究的结果将有助于开发新的预防措施和治疗肥胖症及其并发症，特别是2型糖尿病。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 PUBLIC HEALTH RELEVANCE: Obesity and its associated metabolic disorders such as Type 2 diabetes constitute a serious threat to global health. The studies proposed in this grant application will investigate how subset immune cells called Natural Killer T (NKT) cells, which react to lipids and play a critical role in establishing immune and inflammatory responses, become dysfunctional and in turn influence the development of obesity and Type 2 diabetes. The results from these proposed studies will be instrumental for the development of novel preventive measures and therapies for obesity and its complications, in particular Type 2 diabetes. Page 1