CXC Ligand 5 Is an Adipose-Tissue Derived Factor that Links Obesity to Insulin Resistance

• Published in: Cell metabolism Vol. 9; no. 4; pp. 339 - 349
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2009; Elsevier
• Subjects: Adipose Tissue - cytology; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Animals; Biochemistry, Molecular Biology; Chemokine CXCL5 - deficiency; Chemokine CXCL5 - genetics; Chemokine CXCL5 - metabolism; Gene Expression Regulation - drug effects; Humans; HUMDISEASE; Insulin Resistance; Life Sciences; Macrophages - drug effects; Macrophages - metabolism; Mice; Obesity - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Thiazolidinediones - pharmacology; Tumor Necrosis Factor-alpha - pharmacology; HUMDISEASE; Messenger/genetics/metabolism Signal Transduction/drug effects Thiazolidinediones/pharmacology Tumor Necrosis Factor-alpha/pharmacology; Adipose Tissue/cytology/drug effects/metabolism Animals Chemokine CXCL5/deficiency/genetics/metabolism Gene Expression Regulation/drug effects Humans Insulin Resistance Macrophages/drug effects/metabolism Mice Obesity/metabolism RNA
• ISSN: 1550-4131; 1932-7420
• 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.