The B Cell Insulin Receptor in Health and in Insulin Resistance

项目摘要/摘要 肥胖是一个主要的全球健康问题。当人们变得肥胖时，身体对胰岛素没有很好的反应， 称为胰岛素抵抗。这一过程可能导致高血糖引发2型糖尿病，尽管 人们对其根本原因知之甚少。我们已经证明，肝脏和脂肪中的炎症是主要的 胰岛素抵抗的原因。小鼠和人的脂肪组织增加了免疫细胞，T和B细胞， 引起炎症。这种网状炎症是导致肥胖相关胰岛素抵抗的一个关键环节。 目前的研究方案调查了B细胞在肥胖早期和后期的表现。 有趣的是，在这里，我们将胰岛素本身描述为决定肥胖B细胞行为的一个主要因素。 具体地说，我们发现胰岛素与B细胞上的胰岛素受体结合会导致B细胞增殖，使 炎性蛋白和抗体。这一过程有助于建立胰岛素抵抗，因为 当小鼠被基因改造为含有缺乏胰岛素受体的B细胞时，小鼠表现出了改善 在有限的时间内喂食糖尿病引起的高脂肪饮食时的血糖水平。然而，这条相同的途径 也可能会限制长期肥胖期间的免疫细胞功能。事实上，我们在体内看到了胰岛素抵抗 持续时间较长的高脂饮食的免疫细胞，以及对病毒性肺部感染的妥协反应 胰岛素抵抗免疫系统。因此，我们认为胰岛素是启动免疫的一个关键因素。 系统对环境中的危险信号做出反应，并为其功能提供燃料。在建立肥胖的过程中 胰岛素抵抗，胰岛素促进免疫细胞的激活和代谢，从而在以下情况下加剧炎症 对危险信号作出反应；然而，随着该途径变得具有抵抗力，这些具有高碱性的免疫细胞 炎症性语调被削弱，无法应对病毒等新挑战。这一机制也可能解释了 部分原因是肥胖者无法抵抗流感或SARS-2冠状病毒等病毒。 在这项提案中，我们将使用基因工程小鼠模型来研究胰岛素是如何控制B细胞的 肥胖饮食不同时间段的免疫学研究。首先，我们将看看胰岛素控制B的能力 细胞炎症、新陈代谢编程和抗体产生。接下来，我们将了解饮食是如何诱导 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上的 在流感小鼠模型中肺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的相关机制。 导致胰岛素抵抗的B细胞炎症状态。这些实验将给出至关重要的新见解 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 许多情况下，包括致命的病毒，如我们目前的大流行。

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.