INSERM, U907, Nice, France.
Diabetes. 2012 Sep;61(9):2311-9. doi: 10.2337/db11-1455. Epub 2012 Jun 11.
Leukotrienes (LTs) are potent proinflammatory mediators, and many important aspects of innate and adaptive immune responses are regulated by LTs. Key members of the LT synthesis pathway are overexpressed in adipose tissue (AT) during obesity, resulting in increased LT levels in this tissue. We observed that several mouse adipocyte cell lines and primary adipocytes from mice and humans both can secrete large amounts of LTs. Furthermore, this production increases with a high-fat diet (HFD) and positively correlates with adipocyte size. LTs produced by adipocytes play an important role in attracting macrophages and T cells in in vitro chemotaxis assays. Mice that are deficient for the enzyme 5-lipoxygenase (5-LO), and therefore lack LTs, exhibit a decrease in HFD-induced AT macrophage and T-cell infiltration and are partially protected from HFD-induced insulin resistance. Similarly, treatment of HFD-fed wild-type mice with the 5-LO inhibitor Zileuton also results in a reduction of AT macrophages and T cells, accompanied by a decrease in insulin resistance. Together, these findings suggest that LTs represent a novel target in the prevention or treatment of obesity-associated inflammation and insulin resistance.
白三烯（LTs）是强效的促炎介质，许多先天和适应性免疫反应的重要方面都受到 LTs 的调节。在肥胖期间，LT 合成途径的关键成员在脂肪组织（AT）中过度表达，导致该组织中 LT 水平增加。我们观察到，几种小鼠脂肪细胞系和来自小鼠和人类的原代脂肪细胞都可以分泌大量的 LTs。此外，这种产生随着高脂肪饮食（HFD）而增加，并与脂肪细胞大小呈正相关。脂肪细胞产生的 LTs 在体外趋化实验中吸引巨噬细胞和 T 细胞中发挥重要作用。缺乏酶 5-脂氧合酶（5-LO）因此缺乏 LTs 的 5-LO 缺陷小鼠表现出 HFD 诱导的 AT 巨噬细胞和 T 细胞浸润减少，并部分免受 HFD 诱导的胰岛素抵抗。同样，用 5-LO 抑制剂齐留通治疗 HFD 喂养的野生型小鼠也会导致 AT 巨噬细胞和 T 细胞减少，同时胰岛素抵抗降低。总之，这些发现表明 LTs 是预防或治疗肥胖相关炎症和胰岛素抵抗的新靶点。
