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）：当人们研究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变得显而易见。营养不良的人往往免疫抑制，更容易感染，而肥胖和超重的人对炎症性疾病的易感性更高。在美国，营养过剩的危险已经变得明显，根据疾病控制中心的数据，近33%的成年人可以被归类为肥胖或超重，2型糖尿病（T2DM）的发病率正在迅速上升。许多肥胖相关合并症（包括T2DM）似乎与慢性炎症过程相关。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研究自然杀伤T（NKT）细胞（一种识别糖脂抗原的T淋巴细胞亚群）在肥胖及其合并症发展中的功能。我们的第一个目标是调查的机制，NKT细胞活性是由游离脂肪酸调制的间接NKT细胞活化和面板的饱和和不饱和脂肪酸的体外模型。我们的第二个目标是研究NKT细胞活性如何受到特定饮食的影响。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，并将使用流式细胞术、ELISA和离体刺激测定来分析NKT细胞。此外，我们将研究NKT细胞功能的小鼠直接注入饱和和不饱和脂肪酸。在我们的第三个目标中描述的实验将研究NKT细胞在饮食诱导的肥胖和胰岛素抵抗的发展中的作用。在这个目标中，我们将选择饲料缺乏NKT细胞的小鼠，并将研究其免疫和代谢表型。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世纪世纪的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起着核心作用。NKT细胞在多种免疫和炎症性疾病中发挥关键作用，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。这些研究对肥胖和糖尿病领域具有重要意义，并可能导致基于NKT细胞的治疗这些疾病的发展。