Fractalkine in Adipose Inflammation and Insulin Resistance

描述(申请人提供)：最近的研究表明，脂肪炎症在饮食诱导肥胖(DIO)及其代谢和心血管并发症中起着重要作用。例如，趋化因子受体CCR2参与了炎性单核细胞向肥胖脂肪和动脉粥样硬化新生内膜的募集。Fractalkine(CX3CL1)及其单配型受体(CX3CR1)也是动脉粥样硬化的致病因子，新的数据显示CX3CL1-CX3CR1和CCR2在动脉粥样硬化中的相加作用。在初步研究中，我们发现CX3CL1在脂肪炎症中被显著诱导，在人类和啮齿动物肥胖中脂肪CX3CL1增加，脂肪酸和脂肪细胞因子诱导脂肪细胞中的CX3CL1，单核细胞以CX3CR1依赖的方式黏附于人类脂肪细胞，CX3CR1缺乏调节高脂饮食小鼠的脂肪功能和能量平衡。因此，CX3CL1-CX3CR1似乎是极少数与肥胖和动脉粥样硬化有关的趋化因子途径之一，因此是本研究的重点。此外，与其他趋化因子如CCR2不同，CX3CL1-CX3CR1可能是人类相对安全的治疗靶点。我们认为，CX3CL1不依赖CCR2而招募循环单核细胞，驱动脂肪组织巨噬细胞(ATM)的聚集和存活，导致高脂饮食下的胰岛素抵抗和肥胖。这项建议的目的是利用小鼠模型和人类翻译，确定Fractalkine(CX3CL1-CX3CR1)是否调节脂肪炎症及其代谢后果，以及这一作用是否独立于CCR2。目的1研究CX3CL1缺乏和CX3CR1信号转导中断对饮食诱导的小鼠脂肪炎症、能量和葡萄糖稳态以及肥胖的影响。目的2将确定CX3CL1与CCR2在饮食诱导的脂肪炎症、胰岛素抵抗和肥胖小鼠中如何相互作用。目标3将解决CX3CR1功能变异将影响人类脂肪炎症和胰岛素抵抗的假设。我们还将利用小鼠胚胎成纤维细胞来源的脂肪细胞和原代人类脂肪细胞来研究CX3CL1在脂肪细胞诱导单核细胞募集、黏附、激活和存活中的作用。这些研究将确定因果关系和机制，同时为DIO及其并发症中CX3CL1-CX3CR1的临床和治疗发展提供人类背景。 公共卫生相关性：肥胖症中的脂肪炎症导致代谢并发症，包括糖尿病和心脏病。我们假设，Fractalkine可以将炎性细胞招募到组织中，促进高脂肪饮食和肥胖的脂肪炎症和代谢并发症。我们将测试小鼠中Fractalkine信号的缺失或人类中的基因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.