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Netrin-1 in obesity-associated inflammation and metabolic dysfunction

Netrin-1 在肥胖相关炎症和代谢功能障碍中的作用

基本信息

批准号：
388417504
负责人：
Dr. Paul Martin Schlegel
金额：
--
依托单位：
Division of Cardiology
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/388417504?language=en
关键词：
Netrin obesity associated inflammation metabolic

项目摘要

Obesity and its comorbidities, such as insulin resistance, type 2 diabetes and cardiovascular diseases, have dramatically increased over the past decades and are major threats to global health. Chronic inflammation in obesity is mediated by accumulation and retention of proinflammatory monocytes in the adipose tissue. While in lean mice and humans adipose tissue macrophages are mainly anti-inflammatory alternatively activated M2-macrophages, which maintain the insulin sensitivity of adipocytes by the secretion of IL-10, adipose tissue of obese is dominated by pro-inflammatory M1 macrophages contributing to the onset and the persistence of local and systemic chronic inflammation. These actively retained M1 macrophages are a key pathogenic link between obesity and its metabolic sequels. The neuronal guidance protein netrin-1 has dichotomous biological effects on the axonal growth cones in the developing central nervous development depending on the receptor it binds. In previous work we and others were able to demonstrate that netrin-1 impacts inflammatory processes in the periphery with divergent effects in acute and chronic inflammation. Recent work reported that netrin-1 blocks macrophage response to chemokines via Unc5b hindering macrophage egress from adipose tissue and enhancing macrophage survival in chronic inflammation in obesity. Therefore, I propose to identify the mechanisms causing netrin-1 and Unc5b induction on macrophages in obesity. Furthermore, I aim to understand the mechanisms by which netrin-1 and Unc5b sustain obesity related chronic inflammation and metabolic dysfunction. For this, I plan to test whether macrophage specific netrin-1 and/or Unc5b in obesity promote macrophage retention, alter macrophage polarization and metabolism and sustain metabolic dysfunction and systemic inflammation. Understanding mechanisms and identifying crucial pathways by which netrin-1 sustains obesity inflammation in obesity might open novel therapeutics options therapeutic which will be further tested by deleting macrophage specific netrin-1 in already obese mice with established chronic inflammation.

肥胖及其合并症，如胰岛素抵抗、2型糖尿病和心血管疾病，在过去几十年中急剧增加，是对全球健康的主要威胁。肥胖症的慢性炎症是由促炎单核细胞在脂肪组织中的积累和保留介导的。在瘦小鼠和人的脂肪组织中，巨噬细胞主要是抗炎的或者活化的M2-巨噬细胞，其通过分泌IL-10维持脂肪细胞的胰岛素敏感性，而肥胖的脂肪组织主要是促炎的M1巨噬细胞，其有助于局部和全身慢性炎症的发作和持续。这些活跃保留的M1巨噬细胞是肥胖及其代谢后遗症之间的关键致病环节。神经元导向蛋白netrin-1对发育中的中枢神经发育中的轴突生长锥具有二分生物学效应，这取决于其结合的受体。在以前的工作中，我们和其他人能够证明netrin-1影响外周的炎症过程，在急性和慢性炎症中具有不同的作用。最近的工作报道，netrin-1通过Unc 5 b阻断巨噬细胞对趋化因子的反应，阻碍巨噬细胞从脂肪组织中排出，并增强肥胖症慢性炎症中的巨噬细胞存活。因此，我建议确定导致netrin-1和Unc 5 b诱导肥胖症巨噬细胞的机制。此外，我的目标是了解netrin-1和Unc 5 b维持肥胖相关慢性炎症和代谢功能障碍的机制。为此，我计划测试肥胖症中巨噬细胞特异性netrin-1和/或Unc 5 b是否促进巨噬细胞滞留，改变巨噬细胞极化和代谢，并维持代谢功能障碍和全身炎症。了解netrin-1维持肥胖炎症的机制并确定其关键途径可能会开辟新的治疗选择，治疗将通过在已建立慢性炎症的肥胖小鼠中删除巨噬细胞特异性netrin-1进行进一步测试。