Fractalkine in Adipose Inflammation and Insulin Resistance

描述（由申请人提供）：最近的研究表明脂肪炎症在饮食诱导的肥胖症（DIO）及其代谢和心血管并发症中的重要作用。例如，趋化因子受体CCR 2参与炎症单核细胞向肥胖脂肪和动脉粥样硬化新生内膜的募集。Fractalkine（CX 3CL 1）及其单配型受体（CX 3CR 1）也是致动脉粥样硬化的，并且新兴数据显示CX 3CL 1-CX 3CR 1和CCR 2在动脉粥样硬化中的累加作用。在初步研究中，我们证明，CX 3CL 1显着诱导脂肪炎症，脂肪CX 3CL 1增加，在人类和啮齿动物肥胖，脂肪酸和脂肪细胞因子诱导CX 3CL 1在脂肪细胞，单核细胞粘附在人脂肪细胞中的CX 3CR 1依赖性的方式，和CX 3CR 1缺乏调节脂肪功能和能量稳态在高脂肪喂养的小鼠。因此，CX 3CL 1-CX 3CR 1似乎是在肥胖和动脉粥样硬化中涉及的非常少的趋化因子途径之一，因此是该提议的焦点。此外，与其他趋化因子不同，CCR 2、CX 3CL 1-CX 3CR 1可能是一个相对安全的治疗靶点。我们认为CX 3CL 1募集循环单核细胞，独立于CCR 2，驱动脂肪组织巨噬细胞（ATM）的积累和存活，导致胰岛素抵抗和高脂饮食肥胖。该提案的目标是使用小鼠模型和人类翻译，以确定fractalkine（CX 3CL 1-CX 3CR 1）是否调节脂肪炎症及其代谢后果，以及这种作用是否独立于CCR 2。目的1将描述CX 3CL 1缺陷和CX 3CR 1信号传导中断对小鼠饮食诱导的脂肪炎症、能量和葡萄糖稳态以及肥胖的影响。目的2将确定CX 3CL 1如何与CCR 2相互作用，在饮食诱导的脂肪炎症，胰岛素抵抗和肥胖小鼠。目的3将阐明CX 3CR 1的功能变异将影响人类脂肪炎症和胰岛素抵抗的假设。我们还将利用脂肪细胞，来自小鼠胚胎成纤维细胞，和原代人脂肪细胞研究的作用，CX 3CL 1在脂肪细胞诱导单核细胞的募集，粘附，活化和生存。这些研究将定义因果关系和机制，同时为CX 3CL 1-CX 3CR 1在DIO及其并发症中的临床和治疗开发提供人类背景。 公共卫生相关性：脂肪炎症导致代谢并发症，包括糖尿病和肥胖心脏病。我们假设，fractalkine可以将炎症细胞招募到组织中，促进脂肪炎症和高脂饮食和肥胖的代谢并发症。我们将测试小鼠中fractalkine信号的缺失或人类中的遗传变异是否会阻止脂肪炎症及其代谢并发症。这项工作可能会导致新的治疗方法，阻断fractalkine的作用，从而减少肥胖症的并发症，包括糖尿病和心脏病。

DESCRIPTION (provided by applicant): Recent work suggests a prominent role for adipose inflammation in diet induced obesity (DIO) and its metabolic and cardiovascular complications. For example, CCR2, a chemokine receptor, has been implicated in inflammatory monocyte recruitment into obese adipose and into neointima of atherosclerosis. Fractalkine (CX3CL1) and its monogamous receptor (CX3CR1) are also atherogenic and emerging data show additive roles for CX3CL1-CX3CR1 and CCR2 in atherosclerosis. In preliminary studies, we demonstrate that CX3CL1 is markedly induced in adipose inflammation, adipose CX3CL1 is increased in human and rodent obesity, fatty acids and adipocytokines induce CX3CL1 in adipocytes, monocytes adhere to human adipocytes in a CX3CR1-dependent manner, and CX3CR1 deficiency modulates adipose function and energy homeostasis in high-fat fed mice. Thus, CX3CL1-CX3CR1 appears to be one of very few chemokine pathways implicated in both obesity and atherosclerosis and therefore is the focus of this proposal. Further, unlike other chemokines e.g., CCR2, CX3CL1-CX3CR1 may be a relatively safe therapeutic target in human. We propose that CX3CL1 recruits circulating monocytes, independent of CCR2, driving adipose tissue macrophage (ATM) accumulation and survival, leading to insulin resistance and obesity on high-fat diet. The goal of this proposal, using mice models and human translation, is to determine whether fractalkine (CX3CL1-CX3CR1) modulates adipose inflammation and its metabolic consequences and if this action is independent of CCR2. Aim 1 will characterize effects of CX3CL1 deficiency and disruption of CX3CR1 signaling on diet-induced adipose inflammation, energy and glucose homeostasis, and obesity in mice. Aim 2 will determine how CX3CL1 interacts with CCR2 in diet-induced adipose inflammation, insulin resistance and obesity in mice. Aim 3 will address the hypothesis that functional variation in CX3CR1 will affect adipose inflammation and insulin resistance in humans. We will also utilize adipocytes, derived from mouse embryonic fibroblast, and primary human adipocytes to study the role of CX3CL1 in adipocyte induction of monocyte recruitment, adhesion, activation and survival. These studies will define causality and mechanism while providing the human context for clinical and therapeutic development of CX3CL1-CX3CR1 in DIO and its complications. PUBLIC HEALTH RELEVANCE: Adipose inflammation contributes to metabolic complications including diabetes and heart disease in obesity. We hypothesize that fractalkine, which can recruit inflammatory cells to tissues, promotes adipose inflammation and metabolic complications on high-fat diets and obesity. We will test whether deletion of fractalkine signaling in mice or genetic variation in humans blocks adipose inflammation and its metabolic complications. This work may lead to novel therapeutics that block fractalkine action and thus reduce complications of obesity including diabetes and heart disease.