CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance.
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.
INSERM U834, U896, U834, CRLC Val d'Aurelle, Univ Montpellier 1, F-34295, France.
Carine
C
Chavey
Gwendal
G
Lazennec
Sylviane
S
Lagarrigue
Cyrielle
C
Clapé
Irena
I
Iankova
Jacques
J
Teyssier
Jean-Sébastien
JS
Annicotte
Julien
J
Schmidt
Chikage
C
Mataki
Hiroyasu
H
Yamamoto
Rosario
R
Sanches
Anna
A
Guma
Vladimir
V
Stich
Michaela
M
Vitkova
Bénédicte
B
Jardin-Watelet
Eric
E
Renard
Robert
R
Strieter
Antoinette
A
Tuthill
Gôkhan S
GS
Hotamisligil
Antonio
A
Vidal-Puig
Antonio
A
Zorzano
Dominique
D
Langin
Lluis
L
Fajas
D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D054365:Chemokine CXCL5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone