Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Seoul, Korea.
Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, Korea.
Obesity (Silver Spring). 2018 Feb;26(2):378-386. doi: 10.1002/oby.22103. Epub 2017 Dec 27.
Adipose tissue inflammation induced by macrophage infiltration through the C-C motif chemokine receptor (CCR) 2 or CCR5 pathway has a pivotal role in obesity-related disease and insulin resistance. Here, the effect of PF4178903, a dual CCR2/CCR5 antagonist, on obesity and insulin resistance was evaluated.
Forty male C57BL/6J mice were divided into four groups as follows: (1) regular diet (RD), (2) RD with PF4178903, (3) high-fat diet (HFD), and (4) HFD with PF4178903. All mice were sacrificed 12 weeks after the beginning of the experiment. Biochemical analyses and adipose tissue examinations were performed.
After treatment with PF4178903, both body weight and adipocyte size in white adipose tissue were decreased in HFD-fed mice. Furthermore, PF4178903 treatment reduced adipose tissue macrophages (ATMs) and lowered serum proinflammatory cytokines in HFD-fed mice. PF4178903 treatment significantly improved HFD-induced insulin resistance and glucose intolerance. Fluorescence-activated cell sorter analysis revealed that PF4178903 treatment reduced the CD8 + T cell fraction in white adipose tissue of HFD-fed mice. PF4178903 treatment reduced M1-polarized macrophages while inducing an M2-dominant shift in macrophages within white adipose tissue in HFD-fed mice.
Dual CCR2/CCR5 antagonism ameliorates insulin resistance and inflammation in obesity by regulating ATM recruitment and polarization in white adipose tissue.
脂肪组织炎症是由巨噬细胞浸润通过 C-C 基序趋化因子受体（CCR）2 或 CCR5 途径引起的，在肥胖相关疾病和胰岛素抵抗中起关键作用。在这里，评估了双重 CCR2/CCR5 拮抗剂 PF4178903 对肥胖和胰岛素抵抗的影响。
将 40 只雄性 C57BL/6J 小鼠分为四组：（1）普通饮食（RD），（2）RD 加 PF4178903，（3）高脂肪饮食（HFD），和（4）HFD 加 PF4178903。所有小鼠在实验开始后 12 周被处死。进行生化分析和脂肪组织检查。
在用 PF4178903 治疗后，HFD 喂养的小鼠的体重和白色脂肪组织中的脂肪细胞大小均降低。此外，PF4178903 治疗减少了脂肪组织巨噬细胞（ATMs）并降低了 HFD 喂养小鼠的血清促炎细胞因子。PF4178903 治疗显著改善了 HFD 诱导的胰岛素抵抗和葡萄糖不耐受。荧光激活细胞分选分析显示，PF4178903 治疗减少了 HFD 喂养小鼠白色脂肪组织中的 CD8+T 细胞分数。PF4178903 治疗减少了 M1 极化的巨噬细胞，同时诱导了 HFD 喂养小鼠白色脂肪组织中 M2 占主导地位的巨噬细胞极化转变。
双重 CCR2/CCR5 拮抗作用通过调节白色脂肪组织中 ATMs 的募集和极化来改善肥胖症中的胰岛素抵抗和炎症。
