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.

项目摘要 /摘要 肥胖是全球主要的健康问题。当人们肥胖时，身体对胰岛素的反应不佳， 称为胰岛素抵抗。这个过程可能导致高血糖触发2型糖尿病，尽管 基本原因知之甚少。我们已经表明肝脏和脂肪中的炎症是主要的 胰岛素抵抗的原因。小鼠和人们的脂肪组织增加了免疫细胞，T和B细胞， 引起炎症。这种净炎症是导致与肥胖相关的胰岛素耐药性的一个关键联系。 当前的研究建议研究了B细胞在肥胖症的早期和更晚期的表现。 有趣的是，在这里，我们将胰岛素本身描述为决定B细胞在肥胖症中行为的主要因素。 具体而言，我们表明胰岛素与其在B细胞上的受体结合会导致B细胞增殖，使其成为 炎性蛋白和抗体。此过程有助于建立胰岛素抵抗，因为 当小鼠经过基因工程以含有缺乏胰岛素受体的B细胞时，小鼠显示出改善 血糖水平在有限的时间内喂养糖尿病时诱发高脂饮食。但是，同样的途径 长期肥胖期间还可以限制免疫细胞功能。确实，我们看到内部胰岛素抵抗 持续时间较长脂肪饮食的免疫细胞，以及对小鼠病毒肺部感染的反应损害 胰岛素抵抗免疫系统。这就是我们认为胰岛素是刺激免疫的关键因素 响应环境中危险信号并加剧其功能的系统。在建立肥胖期间 以及胰岛素抵抗，胰岛素促进激活和免疫细胞的代谢增强炎症 回应危险信号；但是，随着途径的抗性，这些具有高基础的免疫细胞 炎症性语调瘫痪，以应对病毒等新挑战。这种机制也可能解释 在某种程度上，肥胖不能与诸如影响力或SARS-2冠状病毒之类的病毒作斗争。 在此提案中，我们将使用一般设计的鼠标模型来绘制胰岛素如何控制B细胞 在肥胖饮食不同持续时间内的免疫学。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引起 肥胖是通过胰岛素作用对B细胞进行控制以控制血糖的。这个目的包括映射 免疫靶基因上的胰岛素受体对接位点。然后，我们将表征免疫学 在肺部病毒感染过程中，免疫细胞胰岛素抵抗的后果在小鼠的造影症模型中。 最后，我们将确定与肥胖相关的危险模式信号传导的相对机械作用 促进胰岛素耐药B细胞炎症状态。这些实验将提供至关重要的新见解 进入免疫细胞对肥胖的影响，以及肥胖如何潜在地夹住免疫力，这与 许多疾病，包括致命病毒，例如我们当前的大流行。