Nagashimada Mayumi, Sawamoto Kazuki, Ni Yinhua, Kitade Hironori, Nagata Naoto, Xu Liang, Kobori Masuko, Mukaida Naofumi, Yamashita Tatsuya, Kaneko Shuichi, Ota Tsuguhito
Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan.
Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Endocrinology. 2021 Jun 1;162(6). doi: 10.1210/endocr/bqab064.
The CX3CL1-CX3CR1 system plays an important role in disease progression by regulating inflammation both positively and negatively. We reported previously that C-C chemokine receptors 2 and 5 promote obesity-associated adipose tissue inflammation and insulin resistance. Here, we demonstrate that CX3CL1-CX3CR1 signaling is involved in adipose tissue inflammation and insulin resistance in obese mice via adipose tissue macrophage recruitment and M1/M2 polarization. Cx3cl1 expression was persistently decreased in the epididymal white adipose tissue (eWAT) of high-fat diet-induced obese (DIO) mice, despite increased expression of other chemokines. Interestingly, in Cx3cr1-/- mice, glucose tolerance, insulin resistance, and hepatic steatosis induced by DIO or leptin deficiency were exacerbated. CX3CL1-CX3CR1 signaling deficiency resulted in reduced M2-polarized macrophage migration and an M1-dominant shift of macrophages within eWAT. Furthermore, transplantation of Cx3cr1-/- bone marrow was sufficient to impair glucose tolerance, insulin sensitivity, and regulation of M1/M2 status. Moreover, Cx3cl1 administration in vivo led to the attenuation of glucose intolerance and insulin resistance. Thus, therapy targeting the CX3CL1-CX3CR1 system may be beneficial in the treatment of type 2 diabetes by regulating M1/M2 macrophages.
CX3CL1-CX3CR1系统通过正负调节炎症在疾病进展中发挥重要作用。我们之前报道过C-C趋化因子受体2和5促进肥胖相关的脂肪组织炎症和胰岛素抵抗。在此，我们证明CX3CL1-CX3CR1信号通过脂肪组织巨噬细胞募集和M1/M2极化参与肥胖小鼠的脂肪组织炎症和胰岛素抵抗。尽管其他趋化因子的表达增加，但在高脂饮食诱导的肥胖（DIO）小鼠的附睾白色脂肪组织（eWAT）中，Cx3cl1的表达持续降低。有趣的是，在Cx3cr1基因敲除小鼠中，由DIO或瘦素缺乏诱导的葡萄糖耐量、胰岛素抵抗和肝脂肪变性加剧。CX3CL1-CX3CR1信号缺陷导致eWAT内M2极化巨噬细胞迁移减少和巨噬细胞向M1优势转变。此外，移植Cx3cr1基因敲除小鼠的骨髓足以损害葡萄糖耐量、胰岛素敏感性和M1/M2状态的调节。而且，体内给予Cx3cl1可减轻葡萄糖不耐受和胰岛素抵抗。因此，靶向CX3CL1-CX3CR1系统的治疗可能通过调节M1/M2巨噬细胞对2型糖尿病的治疗有益。
