The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity.
The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity.
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DOI：
10.1371/journal.pone.0136304
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yokode M
中科院分区：
文献类型：
--
作者：
Yasui M;Tamura Y;Minami M;Higuchi S;Fujikawa R;Ikedo T;Nagata M;Arai H;Murayama T;Yokode M
随着体重的增加，巨噬细胞在脂肪组织中积累。在那里，活化的巨噬细胞分泌许多促炎细胞因子和趋化因子，引起慢性炎症和胰岛素抵抗。前列腺素E2通过EP 4抑制巨噬细胞活化;然而，EP 4信号在胰岛素抵抗和2型糖尿病中的作用仍然未知。在这项研究中，我们用EP 4选择性激动剂ONO-AE 1 -329治疗db/db小鼠4周，以探索EP 4信号在体内肥胖相关炎症中的作用。EP 4激动剂的给药不影响体重增加或食物摄入;然而，在EP 4激动剂治疗组中，葡萄糖耐量和胰岛素抵抗比溶媒治疗组显著改善。此外，给予EP 4激动剂可抑制F4/80阳性巨噬细胞的积聚和白色脂肪组织中冠状结构的形成，并且脂肪细胞显著较小。EP 4激动剂的治疗增加了抗炎M2巨噬细胞的数量，并且在包括巨噬细胞的白色脂肪组织的基质血管部分中，其显著降低了促炎细胞因子和趋化因子的水平。此外，EP 4激活增加了脂联素和过氧化物酶增殖物激活受体在白色脂肪组织中的表达。接下来，我们检查了体外M1/M2极化测定以研究EP 4信号传导对确定巨噬细胞功能表型的影响。用EP 4激动剂处理增强了野生型腹腔巨噬细胞的M2极化，而EP 4缺陷型巨噬细胞对M2极化不太敏感。值得注意的是，拮抗过氧化物酶增殖物激活受体δ活性抑制了EP 4信号介导的向M2巨噬细胞极化的转变。因此，我们的研究结果表明，EP 4信号通过调节巨噬细胞的募集和极化在肥胖相关的脂肪组织炎症和胰岛素抵抗中起着关键作用。EP 4信号传导的激活有望用于治疗肥胖和2型糖尿病。
With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist–treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle–treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator–activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator–activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.