NKT cells, fatty acids, and insulin resistance

NKT 细胞、脂肪酸和胰岛素抵抗

• 批准号: 7615975
• 负责人: Curtis Lee Gabriel
• 金额: $ 3.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615975
• 关键词: Abbreviations; Acids; Adipose tissue; Adult; Animal Model; Antigen-Presenting Cells; Antigens; Biological Assay; Body Composition; Cell Count; Cell Therapy; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Comorbidity; Complex; Data; Development; Diabetes Mellitus; Diet; Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Enzyme-Linked Immunosorbent Assay; Epidemic; Fat-Restricted Diet; Fatty Acids; Fish Oils; Flow Cytometry; Foundations; Galactosylceramides; Genes; Glycolipids; Goals; Immune; Immune Cell Activation; Immune system; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Infusion procedures; Insulin; Insulin Resistance; Laboratories; Lead; Link; Lipids; Lipopolysaccharides; Malnutrition; Mediating; Metabolic; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional; Nutritional status; Obesity; Omega-3 Fatty Acids; Overnutrition; Overweight; Pathogenesis; Pathway interactions; Phenotype; Play; Polymerase Chain Reaction; Polyunsaturated Fatty Acids; Predisposition; Process; Public Health; Rattus; Resistance; Role; Signal Transduction; Signaling Molecule; System; T-Cell Activation; T-Lymphocyte Subsets; TLR4 gene; Testing; Thinking; Time; United States; United States Environmental Protection Agency; Unsaturated Fatty Acids; Weights and Measures; base; dietary supplements; feeding; human disease; immunosuppressed; in vitro Model; in vivo; insight; killer T cell; lard; macrophage; nonalcoholic steatohepatitis; obesity treatment; prevent; protective effect; research study; saturated fat; toll-like receptor 4

DESCRIPTION (provided by applicant): The links between nutritional status and immune system function become apparent when one examines the diametrically opposite epidemics of malnutrition and overnutrition. Undernourished individuals tend to be immunosuppressed and more susceptible to infections, whereas obese and overweight individuals have higher susceptibility to inflammatory diseases. The dangers of overnutrition have become apparent in the United States where, according the Centers for Disease Control, nearly 33% of adults can be classified as obese or overweight and the incidence of type 2 diabetes mellitus (T2DM) is rapidly rising. Many obesity related comorbidities, including T2DM, appear to be associated with chronic inflammatory processes. The mechanistic relationship between obesity and inflammation involves a complex network of cells and signaling molecules from both the immune system and metabolic system. The long-term goals of this project are to examine the function of natural killer T (NKT) cells, a T lymphocyte subset which recognizes glycolipid antigens, in the development of obesity and its comorbidities. We first aim to investigate the mechanism by which NKT cell activity is modulated by free fatty acids by using an in vitro model of indirect NKT cell activation and a panel of saturated and unsaturated fatty acids. Our second aim will investigate how NKT cell activity is influenced by specific diets. To achieve this goal, we will feed mice a lard diet, a fish oil diet or a low-fat diet, and will analyze NKT cells using flow cytometry, ELISA and ex vivo stimulation assays. Additionally, we will study NKT cell function in mice directly infused with saturated and unsaturated fatty acids. The experiments described in our third aim will investigate the role of NKT cells in the development of diet-induced obesity and insulin resistance. In this aim, we will feed selected diets to mice deficient in NKT cells and will investigate their immunological and metabolic phenotype. Specifically, we will measure weight gain, body composition, insulin resistance, and expression of pro-inflammatory genes in adipose tissue. Obesity is a preeminent public health concern of the 21st century, and inflammation appears to play a central role in the development of both obesity and its comorbidities. NKT cells play key roles in a variety of immune and inflammatory diseases and we aim to study the function of these cells in the pathogenesis of obesity and diabetes. These studies are of great importance to the fields of obesity and diabetes, and could lead to the development of NKT cell-based therapies for these diseases.

描述（由申请人提供）：当人们检查营养不良和营养过剩这两种截然相反的流行病时，营养状况和免疫系统功能之间的联系就变得显而易见。营养不良的人往往免疫抑制，更容易受到感染，而肥胖和超重的人更容易患炎症性疾病。营养过剩的危险在美国已经变得显而易见，根据疾病控制中心的数据，美国近 33% 的成年人属于肥胖或超重，2 型糖尿病 (T2DM) 的发病率正在迅速上升。许多与肥胖相关的合并症，包括 T2DM，似乎与慢性炎症过程有关。肥胖和炎症之间的机制关系涉及来自免疫系统和代谢系统的细胞和信号分子的复杂网络。该项目的长期目标是检查自然杀伤 T (NKT) 细胞（一种识别糖脂抗原的 T 淋巴细胞亚群）在肥胖及其合并症的发展中的功能。我们首先旨在通过使用间接 NKT 细胞激活的体外模型以及一组饱和和不饱和脂肪酸来研究游离脂肪酸调节 NKT 细胞活性的机制。我们的第二个目标是研究特定饮食如何影响 NKT 细胞活性。为了实现这一目标，我们将给小鼠喂猪油饮食、鱼油饮食或低脂饮食，并使用流式细胞术、ELISA 和离体刺激试验来分析 NKT 细胞。此外，我们将研究直接注入饱和和不饱和脂肪酸的小鼠的 NKT 细胞功能。我们的第三个目标中描述的实验将研究 NKT 细胞在饮食引起的肥胖和胰岛素抵抗的发展中的作用。为此，我们将向缺乏 NKT 细胞的小鼠喂食选定的饮食，并研究它们的免疫学和代谢表型。具体来说，我们将测量体重增加、身体成分、胰岛素抵抗和脂肪组织中促炎基因的表达。肥胖是 21 世纪一个突出的公共卫生问题，炎症似乎在肥胖及其合并症的发展中发挥着核心作用。 NKT 细胞在多种免疫和炎症疾病中发挥着关键作用，我们的目标是研究这些细胞在肥胖和糖尿病发病机制中的功能。这些研究对于肥胖和糖尿病领域非常重要，并可能导致针对这些疾病的基于 NKT 细胞的疗法的开发。