Disruption of CXC motif chemokine ligand-14 in mice ameliorates obesity-induced insulin resistance
Disruption of CXC motif chemokine ligand-14 in mice ameliorates obesity-induced insulin resistance
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DOI：
10.1074/jbc.m700412200
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发表时间：
2007-10-19
影响因子：
4.8
通讯作者：
Hara, Takahiko
中科院分区：
文献类型：
--
作者：
Nara, Noriko;Nakayama, Yuki;Hara, Takahiko
在肥胖个体中，白色脂肪组织（WAT）被大量巨噬细胞浸润，导致炎症反应增强，从而导致胰岛素抵抗。本研究表明，与常规饮食的瘦小鼠相比，高脂饮食（HFD）的肥胖小鼠WAT中靶向组织巨噬细胞的CXC基序趋化因子配体-14 （CXCL14）的表达升高。我们发现，饲喂hfd的cxcl14缺陷小鼠的WAT巨噬细胞动员受损，胰岛素反应性改善。胰岛素刺激的骨骼肌Akt激酶磷酸化在hfd喂养的CXCL14（+/-）小鼠中严重减弱，而在hfd喂养的CXCL14（-/-）小鼠中没有减弱。HFD喂养后CXCL14（-/-）小鼠的胰岛素敏感表型在雌性小鼠中明显，而在雄性小鼠中不明显。饲喂hfd的CXCL14（+/-）小鼠可免受高血糖、高胰岛素血症和低脂联素血症的影响，WAT中循环视黄醇结合蛋白-4水平和白细胞介素-6表达水平均未升高。在骨骼肌中转基因过表达CXCL14可恢复CXCL14（+/-）小鼠肥胖诱导的胰岛素抵抗。CXCL14在培养的肌细胞中减弱胰岛素刺激的葡萄糖摄取，在培养的脂肪细胞中也有较小程度的减弱。这些结果表明，CXCL14是WAT巨噬细胞的关键化学引诱剂，也是一种主要在骨骼肌中起作用的葡萄糖代谢的新型调节剂。
In obese individuals, white adipose tissue (WAT) is infiltrated by large numbers of macrophages, resulting in enhanced inflammatory responses that contribute to insulin resistance. Here we show that expression of the CXC motif chemokine ligand-14 (CXCL14), which targets tissue macrophages, is elevated in WAT of obese mice fed a high fat diet (HFD) compared with lean mice fed a regular diet. We found that HFD-fed CXCL14-deficient mice have impaired WAT macrophage mobilization and improved insulin responsiveness. Insulin-stimulated phosphorylation of Akt kinase in skeletal muscle was severely attenuated in HFD-fed CXCL14(+/-) mice but not in HFD-fed CXCL14(-/-) mice. The insulin-sensitive phenotype of CXCL14(-/-) mice after HFD feeding was prominent in female mice but not in male mice. HFD-fed CXCL14(+/-) mice were protected from hyperglycemia, hyperinsulinemia, and hypoadiponectinemia and did not exhibit increased levels of circulating retinol-binding protein-4 and increased expression of interleukin-6 in WAT. Transgenic overexpression of CXCL14 in skeletal muscle restored obesity-induced insulin resistance in CXCL14(+/-) mice. CXCL14 attenuated insulin-stimulated glucose uptake in cultured myocytes and to a lesser extent in cultured adipocytes. These results demonstrate that CXCL14 is a critical chemoattractant of WAT macrophages and a novel regulator of glucose metabolism that functions mainly in skeletal muscle.