The B Cell Insulin Receptor in Health and in Insulin Resistance

B 细胞胰岛素受体在健康和胰岛素抵抗中的作用

• 批准号: 10367879
• 负责人: Dan Winer
• 金额: $ 62.36万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367879
• 关键词: 2019-nCoV; Activities of Daily Living; Acute; Adipose tissue; Adjuvant; Aging; Antibodies; Antibody Formation; Automobile Driving; B-Cell Activation; B-Lymphocytes; Behavior; Beta Cell; Binding; Blood Glucose; Brain; COVID-19; COVID-19 risk; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Centers for Disease Control and Prevention (U.S.); Chronic; Coronavirus; Development; Diabetes Mellitus; Diet; Disease; Docking; Environment; Fatty acid glycerol esters; Frequencies; Functional disorder; Genes; Genetic Transcription; Genetically Engineered Mouse; Glucose; Health; High Fat Diet; Homeostasis; Human; Hyperinsulinism; Immune; Immune Targeting; Immune system; Immunity; Immunoglobulin G; Immunologics; Immunology; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Knockout Mice; Knowledge; Lead; Link; Lipids; Liver; Longevity; Lung; Lung infections; Maps; Metabolic; Metabolism; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Translocation; Obese Mice; Obesity; Organism; Pathogenicity; Pathway interactions; Pattern; Persons; Play; Process; Production; Proliferating; Proteins; Receptor Signaling; Reporting; Research Proposals; Resistance; Risk Factors; Role; Severe Acute Respiratory Syndrome; Signal Pathway; Signal Transduction; Site; T-Lymphocyte; Time; Tissues; Toll-like receptors; Viral; Virus; Virus Diseases; Visceral; Work; cytokine; diet-induced obesity; experimental study; fighting; global health; high risk; immunoregulation; improved; influenza infection; insight; insulin signaling; mortality risk; mouse model; novel; novel therapeutics; obesogenic; pandemic disease; receptor; response

PROJECT SUMMARY / ABSTRACT Obesity is a major global health concern. When people become obese, the body fails to respond well to insulin, called insulin resistance. This process can lead to high blood sugar triggering type 2 diabetes, though the underlying causes are poorly understood. We have shown that inflammation in the liver and fat are major causes of insulin resistance. Fat tissue in mice and people have increased immune cells, T and B cells, that cause inflammation. This net inflammation is one key link leading to obesity related insulin resistance. The current research proposal investigates how the B cell behaves during early and later stages of obesity. Interestingly, here we describe insulin itself as a major factor dictating the behavior of B cells in obesity. Specifically, we show that insulin binding to its receptor on B cells causes the B cells to proliferate, make inflammatory proteins and antibodies. This process contributes to establishment of insulin resistance since when mice are genetically engineered to contain B cells lacking insulin receptors, the mice show improved blood sugar levels when fed a diabetes inducing high fat diet for a limited time. However, this same pathway may also limit immune cell function during longstanding obesity. Indeed, we see insulin resistance inside immune cells with longer duration high fat diet, and compromised response to viral lung infection in mice with insulin resistant immune systems. Thus, we believe that insulin is one critical factor which primes the immune system to respond to danger signals in the environment and fuel its function. During establishment of obesity and insulin resistance, insulin boost activation and metabolism of immune cells to heighten inflammation when responding to danger signals; however, as the pathway becomes resistant, these immune cells with high basal inflammatory tone are crippled to respond to new challenge such as virus. This mechanism also likely explains in part why the obese cannot fight off viruses like influenza or SARS-2 coronaviruses. In this proposal we will use genetically engineered mouse models to map out how insulin controls B cell immunology during different durations of obesogenic diet. First, we will look at insulin’s capacity to control B cell inflammation, metabolic programming and antibody production. Next, we will understand how diet induced obesity communicates via insulin action on B cells to control blood sugar. This aim includes mapping out insulin receptor docking sites on immunological target genes. Then we will characterize the immunological consequences of immune cell insulin resistance during lung virus infection in a mouse model of influenza. Finally, we will determine the relative mechanistic roles for obesity related danger pattern signaling in contributing to the insulin resistant B cell inflammatory state. These experiments will give crucial new insights into immune cell influence on obesity, and how obesity potentially cripples immunity, which has relevance to many conditions, including lethal viruses such as our current pandemic.

项目总结/摘要 肥胖是一个主要的全球健康问题。当人们变得肥胖时，身体对胰岛素的反应不佳， 叫做胰岛素抵抗。这一过程可能导致高血糖引发2型糖尿病，尽管 根本原因知之甚少。我们已经表明，肝脏和脂肪的炎症是主要的 胰岛素抵抗的原因老鼠和人的脂肪组织增加了免疫细胞，T和B细胞， 引起炎症。这种净炎症是导致肥胖相关胰岛素抵抗的一个关键环节。 目前的研究计划调查了B细胞在肥胖早期和晚期的行为。 有趣的是，在这里我们将胰岛素本身描述为决定肥胖症中B细胞行为的主要因素。 具体地说，我们发现胰岛素与B细胞上的受体结合，导致B细胞增殖， 炎症蛋白和抗体。这一过程有助于建立胰岛素抵抗，因为 当小鼠被基因工程改造成含有缺乏胰岛素受体的B细胞时，小鼠表现出改善的 当在有限的时间内喂食诱发糖尿病的高脂肪饮食时血糖水平。然而，同样的途径 也可能限制免疫细胞功能在长期肥胖。事实上，我们看到胰岛素抵抗， 免疫细胞与持续时间较长的高脂肪饮食，并损害反应的病毒肺部感染的小鼠， 胰岛素抵抗的免疫系统。因此，我们认为胰岛素是启动免疫系统的一个关键因素。 系统对环境中的危险信号作出反应，并为其功能提供动力。在肥胖建立期间 和胰岛素抵抗，胰岛素增强免疫细胞的激活和代谢，以提高炎症时， 对危险信号做出反应;然而，随着通路变得具有抵抗力，这些具有高基础免疫细胞的免疫细胞 炎性音调被削弱以响应新挑战如病毒。这种机制也可能解释了 这也是为什么肥胖者不能抵抗流感或SARS-2冠状病毒的部分原因。 在这个建议中，我们将使用基因工程小鼠模型来绘制胰岛素如何控制B细胞 免疫学在不同时间的肥胖饮食。首先，我们将研究胰岛素控制B的能力 细胞炎症、代谢编程和抗体产生。接下来，我们将了解饮食如何诱导 肥胖通过胰岛素作用于B细胞来控制血糖。这一目标包括制定 免疫靶基因上的胰岛素受体对接位点。然后我们将描述免疫学 流感小鼠模型中肺部病毒感染期间免疫细胞胰岛素抵抗的后果。 最后，我们将确定肥胖相关的危险模式信号传导的相对机制作用， 导致胰岛素抵抗B细胞炎症状态。这些实验将提供至关重要的新见解 研究免疫细胞对肥胖的影响，以及肥胖如何潜在地削弱免疫力，这与 包括致命的病毒，例如我们目前的大流行病。