武汉云克隆科技股份有限公司

Abstract：During obesity, macrophage accumulation in adipose tissue propagates the chronic inflammation and insulin resistance associated with type 2 diabetes. The factors, however, that regulate the accrual of macrophages in adipose tissue are not well understood. Here we show that the neuroimmune guidance cue netrin-1 is highly expressed in obese but not lean adipose tissue of humans and mice, where it directs the retention of macrophages. Netrin-1, whose expression is induced in macrophages by the saturated fatty acid palmitate, acts via its receptor Unc5b to block their migration. In a mouse model of diet-induced obesity, we show that adipose tissue macrophages exhibit reduced migratory capacity, which can be restored by blocking netrin-1. Furthermore, hematopoietic deletion of Ntn1 facilitates adipose tissue macrophage emigration, reduces inflammation and improves insulin sensitivity. Collectively, these findings identify netrin-1 as a macrophage retention signal in adipose tissue during obesity that promotes chronic inflammation and insulin resistance.

摘要：对于肥胖患者，巨噬细胞在脂肪组织中的积聚导致慢性炎症和胰岛素抗性与2型糖尿病相关。然而，调节脂肪组织中巨噬细胞的聚集的相关机制尚不清楚。我们发现神经免疫导索Netrin-1在人和小鼠的肥胖脂肪而不在瘦脂肪组织中高度表达，它指导着巨噬细胞的滞留。在巨噬细胞中，Netrin-1由饱和脂肪酸棕榈酸酯诱导表达，通过其受体Unc5b来阻止巨噬细胞迁移。在饮食型肥胖的小鼠模型中，我们发现可以通过阻断Netrin-1来恢复脂肪组织中巨噬细胞降低的迁移能力。此外，Ntn1的造血缺失可以促进脂肪组织巨噬细胞迁移，减少炎症，提高胰岛素敏感性。这些发现表明Netrin-1可以作为脂肪组织中巨噬细胞的滞留信号。

使用试剂原文信息：ELISA assays. Insulin (90080; Crystal Chem), adiponectin (ab108785;Abcam), FFA (SFA­1; Zen Bio), TNF-a (88­7064­76; eBioscience) and netrin­1(E91827Mu; USCN Life science) levels were measured in the serum or cell supernatants using mouse standards according to manufacturer’s guidelines.