Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan.
Diabetes. 2012 Jul;61(7):1680-90. doi: 10.2337/db11-1506. Epub 2012 Apr 3.
C-C motif chemokine receptor (CCR)2 and its ligand, monocyte chemoattractant protein (MCP)-1, are pivotal for adipose tissue macrophage (ATM) recruitment and the development of insulin resistance. However, other chemokine systems also may play a role in these processes. In this study, we investigated the role of CCR5 in obesity-induced adipose tissue inflammation and insulin resistance. We analyzed expression levels of CCR5 and its ligands in white adipose tissue (WAT) of genetically (ob/ob) and high-fat (HF) diet-induced obese (DIO) mice. Furthermore, we examined the metabolic phenotype of Ccr5(-/-) mice. CCR5 and its ligands were markedly upregulated in WAT of DIO and ob/ob mice. Fluorescence-activated cell sorter analysis also revealed that DIO mice had a robust increase in CCR5(+) cells within ATMs compared with chow-fed mice. Furthermore, Ccr5(-/-) mice were protected from insulin resistance, glucose intolerance, and hepatic steatosis induced by HF feeding. The effects of loss of CCR5 were related to both reduction of total ATM content and an M2-dominant shift in ATM polarization. It is noteworthy that transplantation of Ccr5(-/-) bone marrow was sufficient to protect against impaired glucose tolerance. CCR5 plays a critical role in ATM recruitment and polarization and subsequent development of insulin resistance.
C-C 基序趋化因子受体 (CCR)2 及其配体单核细胞趋化蛋白-1 (MCP-1) 对于脂肪组织巨噬细胞 (ATM) 的募集和胰岛素抵抗的发展至关重要。然而，其他趋化因子系统也可能在这些过程中发挥作用。在这项研究中，我们研究了 CCR5 在肥胖引起的脂肪组织炎症和胰岛素抵抗中的作用。我们分析了遗传肥胖 (ob/ob) 和高脂肪 (HF) 饮食诱导肥胖 (DIO) 小鼠白色脂肪组织 (WAT) 中 CCR5 及其配体的表达水平。此外，我们还研究了 Ccr5(-/-) 小鼠的代谢表型。CCR5 及其配体在 DIO 和 ob/ob 小鼠的 WAT 中明显上调。荧光激活细胞分选分析还显示，与正常饮食喂养的小鼠相比，DIO 小鼠的 ATMs 中 CCR5(+)细胞数量显著增加。此外，Ccr5(-/-) 小鼠对 HF 喂养引起的胰岛素抵抗、葡萄糖不耐受和肝脂肪变性具有保护作用。CCR5 缺失的作用与总 ATM 含量的减少以及 ATM 极化的 M2 优势转变有关。值得注意的是，Ccr5(-/-) 骨髓的移植足以防止葡萄糖耐量受损。CCR5 在 ATM 的募集和极化以及随后的胰岛素抵抗发展中起着关键作用。
