Chavey Carine, Lazennec Gwendal, Lagarrigue Sylviane, Clapé Cyrielle, Iankova Irena, Teyssier Jacques, Annicotte Jean-Sébastien, Schmidt Julien, Mataki Chikage, Yamamoto Hiroyasu, Sanches Rosario, Guma Anna, Stich Vladimir, Vitkova Michaela, Jardin-Watelet Bénédicte, Renard Eric, Strieter Robert, Tuthill Antoinette, Hotamisligil Gôkhan S, Vidal-Puig Antonio, Zorzano Antonio, Langin Dominique, Fajas Lluis
INSERM U834, U896, U834, CRLC Val d'Aurelle, Univ Montpellier 1, F-34295, France.
Cell Metab. 2009 Apr;9(4):339-49. doi: 10.1016/j.cmet.2009.03.002.
We show here high levels of expression and secretion of the chemokine CXC ligand 5 (CXCL5) in the macrophage fraction of white adipose tissue (WAT). Moreover, we find that CXCL5 is dramatically increased in serum of human obese compared to lean subjects. Conversely, CXCL5 concentration is decreased in obese subjects after a weight reduction program, or in obese non-insulin-resistant, compared to insulin-resistant, subjects. Most importantly we demonstrate that treatment with recombinant CXCL5 blocks insulin-stimulated glucose uptake in muscle in mice. CXCL5 blocks insulin signaling by activating the Jak2/STAT5/SOCS2 pathway. Finally, by treating obese, insulin-resistant mice with either anti-CXCL5 neutralizing antibodies or antagonists of CXCR2, which is the CXCL5 receptor, we demonstrate that CXCL5 mediates insulin resistance. Furthermore CXCR2-/- mice are protected against obesity-induced insulin resistance. Taken together, these results show that secretion of CXCL5 by WAT resident macrophages represents a link between obesity, inflammation, and insulin resistance.
我们在此展示了趋化因子CXC配体5（CXCL5）在白色脂肪组织（WAT）巨噬细胞部分中的高表达和分泌。此外，我们发现与瘦人相比，肥胖人群血清中的CXCL5显著增加。相反，在进行减肥计划后的肥胖受试者中，或在肥胖的非胰岛素抵抗受试者（与胰岛素抵抗受试者相比）中，CXCL5浓度降低。最重要的是，我们证明用重组CXCL5处理可阻断小鼠肌肉中胰岛素刺激的葡萄糖摄取。CXCL5通过激活Jak2/STAT5/SOCS2途径来阻断胰岛素信号传导。最后，通过用抗CXCL5中和抗体或CXCL5受体CXCR2的拮抗剂处理肥胖的胰岛素抵抗小鼠，我们证明CXCL5介导胰岛素抵抗。此外，CXCR2基因敲除小鼠可免受肥胖诱导的胰岛素抵抗影响。综上所述，这些结果表明WAT驻留巨噬细胞分泌的CXCL5代表了肥胖、炎症和胰岛素抵抗之间的联系。
