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.

项目概要/摘要 肥胖是全球主要的健康问题。当人们变得肥胖时，身体就无法对胰岛素做出良好的反应。 这一过程称为胰岛素抵抗，可导致高血糖，从而引发 2 型糖尿病。 我们对根本原因知之甚少，我们已经证明肝脏和脂肪中的炎症是主要原因。 小鼠和人类的脂肪组织中的免疫细胞、T 细胞和 B 细胞增加。 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 B 细胞在肥胖早期和晚期的行为方式。 暗示，在这里我们将胰岛素本身描述为决定肥胖中 B 细胞行为的主要因素。 具体来说，我们表明胰岛素与其 B 细胞上的受体结合会导致 B 细胞增殖，使 此过程有助于建立胰岛素抵抗。 当小鼠经过基因工程改造使其含有缺乏胰岛素受体的 B 细胞时，小鼠表现出改善 然而，在有限的时间内摄入诱导糖尿病的高脂肪饮食时的血糖水平是相同的。 长期肥胖期间也可能会限制免疫细胞功能。事实上，我们在体内看到了胰岛素抵抗。 长期高脂肪饮食的小鼠免疫细胞对病毒性肺部感染的反应受损 因此，我们认为胰岛素是启动免疫系统的关键因素之一。 系统对环境中的危险信号做出反应并在肥胖形成期间促进其功能。 和胰岛素抵抗，胰岛素会促进免疫细胞的激活和新陈代谢，从而加剧炎症 对危险信号做出反应；然而，随着该途径变得有抵抗力，这些具有高基础值的免疫细胞 这种机制也可能解释了炎症反应对病毒等新挑战的反应能力受到削弱。 这也是肥胖者无法抵抗流感或 SARS-2 冠状病毒等病毒的部分原因。 在本提案中，我们将使用基因工程小鼠模型来阐明胰岛素如何控制 B 细胞 首先，我们将研究胰岛素控制 B 的能力。 接下来，我们将了解饮食是如何诱导细胞炎症、代谢编程和抗体产生的。 肥胖通过胰岛素对 B 细胞的作用来控制血糖。这一目标包括制定计划。 然后我们将表征免疫学靶基因上的胰岛素受体对接位点。 流感小鼠模型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危险模式信号传导的相对机制作用 这些实验将提供重要的新见解。 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 许多情况，包括致命病毒，例如我们当前的大流行。