Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance
Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance
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DOI：
10.1096/fj.201500127
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发表时间：
2016-06-01
期刊：
影响因子：
4.8
通讯作者：
Hsieh, Po Shiuan
中科院分区：
文献类型：
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作者：
Chan, Pei-Chi;Hsiao, Fone-Ching;Hsieh, Po Shiuan
我们检测了脂肪细胞环氧合酶-2（考克斯-2）和前列腺素E-2（PGE（2））-前列腺素E受体（EP）3介导的信号转导在肥大和缺氧过程中与肥胖相关的脂肪组织（AT）炎症和胰岛素抵抗的关系。实验用高脂饮食（HFD）诱导的肥胖大鼠、db/db小鼠、人类受试者和3 T3-L1和人类Glasson-Golabi-Behmel综合征（SGBS）脂肪细胞进行;各组用选择性考克斯-2抑制剂[塞来昔布30 mg/kg，半数最大抑制浓度（IC 50）约为0.04 μ M]和EP 3处理（L-798106 100 μ g/kg，IC 50约为0.5 μ M）或短干扰RNA。脂肪细胞考克斯-2和EP 3基因表达与AT TNF-α和单核细胞趋化蛋白-1含量和HFD诱导的肥胖大鼠胰岛素抵抗的稳态模型评估以及人类受试者的体重指数之间存在强正相关。用考克斯-2和EP 3抑制剂治疗显著逆转了db/db小鼠中AT炎性基因和蛋白表达（~ 50%）以及受损的葡萄糖和胰岛素耐受性。抑制考克斯-2可降低HFD大鼠脂肪细胞对巨噬细胞和T细胞的趋化性。靶向抑制脂肪细胞考克斯-2和EP 3在肥大和缺氧过程中逆转了增加的促炎性脂肪因子的释放和减少的脂联素，也抑制了NF-B和缺氧诱导因子-1的转录激活。这些发现表明，脂肪细胞考克斯-2 PGE（2）-EP 3介导的信号传导在肥胖相关AT炎症和胰岛素抵抗的发展中至关重要。C.的方法，萧峰C.的方法，张，H.- M.，Wabitsch，M.，谢国忠脂肪细胞环氧合酶-2和前列腺素E-2-前列腺素E受体3信号在肥胖诱导的脂肪组织炎症和胰岛素抵抗发展中的重要性
We examined the involvement of adipocyte cyclooxygenase-2 (COX-2) and prostaglandin E-2 (PGE(2))-prostaglandin E receptor (EP)3-mediated signaling during hypertrophy and hypoxia in the development of obesity-associated adipose tissue (AT) inflammation and insulin resistance. The experiments were conducted with high-fat diet (HFD)-induced obese rats, db/db mice, human subjects, and 3T3-L1 and the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes; the groups were treated with selective inhibitors of COX-2 [celecoxib 30 mg/kg, half maximal inhibitory concentration (IC50) approximate to 0.04 mu M] and EP3 (L-798106 100 mu g/kg, IC50 approximate to 0.5 mu M) or a short interfering RNA. There were strong, positive correlations between adipocyte COX-2 and EP3 gene expressions and the AT TNF- and monocyte chemotactic protein-1 contents and the homeostatic model assessment for insulin resistance in HFD-induced obese rats, as well as body mass index in human subjects. Treatment with COX-2 and EP3 inhibitors significantly reversed AT inflammatory gene and protein expressions (-50%) and impaired glucose and insulin tolerance in db/db mice. COX-2 inhibition diminished the chemotaxis of adipocytes isolated from HFD rats to macrophages and T cells. Targeting inhibition of adipocyte COX-2 and EP3 during hypertrophy and hypoxia reversed the release of the augmented proinflammatory adipokines and the diminished adiponectin and also suppressed NF-B and hypoxia-inducible factor-1 transcription activation. These findings suggest that adipocyte COX-2 PGE(2)-EP3-mediated signaling is crucially involved in the development of obesity-associated AT inflammation and insulin resistance.Chan, P.-C., Hsiao, F.-C., Chang, H.-M., Wabitsch, M., Hsieh, P. S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E-2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance.