Fractalkine in Adipose Inflammation and Insulin Resistance

分形蛋白在脂肪炎症和胰岛素抵抗中的作用

• 批准号: 8497682
• 负责人: Muredach P Reilly
• 金额: $ 54.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-19 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497682
• 关键词: Address; Adhesions; Adhesives; Adipocytes; Adipose tissue; Affect; Atherosclerosis; Automobile Driving; Binding; Biological; Body Composition; CX3CL1 gene; Cardiovascular system; Cells; Clinical; Coupled; Data; Diabetes Mellitus; Diet; Embryo; Endotoxemia; Energy Metabolism; Etiology; Fasting; Fatty Acids; Fatty acid glycerol esters; Fibroblasts; Fractalkine; Genetic; Genetic Variation; Goals; Heart Diseases; Homeostasis; Human; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Knock-out; Lead; Liver; Metabolic; Modeling; Monitor; Motivation; Motor Activity; Mus; Mutant Strains Mice; Obesity; Participant; Pathway interactions; Population; Property; Recruitment Activity; Reporter; Resistance; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Subgroup; T-Lymphocyte; Testing; Therapeutic; Tissues; Translations; Variant; Wild Type Mouse; Work; attenuation; blood glucose regulation; chemokine; chemokine receptor; feeding; in vivo; insulin sensitivity; macrophage; monocyte; mouse model; novel therapeutics; receptor; small hairpin RNA; therapeutic development; therapeutic target; trait

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.

描述（由申请人提供）：最近的研究表明，脂肪炎症在饮食性肥胖（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与炎性单核细胞募集到肥胖脂肪和动脉粥样硬化新内膜有关。Fractalkine （CX3CL1）及其单配受体（CX3CR1）也可致动脉粥样硬化，新出现的数据显示CX3CL1-CX3CR1和CCR2在动脉粥样硬化中的附加作用。在初步研究中，我们证明了CX3CL1在脂肪炎症中被显著诱导，在人类和啮齿类动物肥胖中脂肪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依赖的方式粘附在人类脂肪细胞上，CX3CR1缺乏调节高脂肪喂养小鼠的脂肪功能和能量稳态。因此，CX3CL1-CX3CR1似乎是与肥胖和动脉粥样硬化有关的极少数趋化因子途径之一，因此是本研究的重点。此外，与CCR2等其他趋化因子不同，CX3CL1-CX3CR1可能是人类相对安全的治疗靶点。我们认为CX3CL1募集循环单核细胞，独立于CCR2，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肪饮食的肥胖。本研究的目的是通过小鼠模型和人类翻译来确定fractalkine （CX3CL1-CX3CR1）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CCR2。目的1将描述CX3CR1缺乏和CX3CR1信号中断对饮食诱导的脂肪炎症、能量和葡萄糖稳态以及小鼠肥胖的影响。目的2将确定CX3CL1与CCR2在小鼠饮食诱导的脂肪炎症、胰岛素抵抗和肥胖中的相互作用。目的3将解决CX3CR1功能变异会影响人类脂肪炎症和胰岛素抵抗的假设。我们还将利用来自小鼠胚胎成纤维细胞和人原代脂肪细胞的脂肪细胞来研究CX3CL1在脂肪细胞诱导单核细胞募集、粘附、激活和存活中的作用。这些研究将明确因果关系和机制，同时为CX3CL1-CX3CR1在DIO及其并发症中的临床和治疗发展提供人类背景。