Adipocytes secrete leukotrienes: contribution to obesity-associated inflammation and insulin resistance in mice.
Leukotrienes (LTs) are potent proinflammatory mediators, and many important aspects of innate and adaptive immune responses are regulated by LTs. Key members of the LT synthesis pathway are overexpressed in adipose tissue (AT) during obesity, resulting in increased LT levels in this tissue. We observed that several mouse adipocyte cell lines and primary adipocytes from mice and humans both can secrete large amounts of LTs. Furthermore, this production increases with a high-fat diet (HFD) and positively correlates with adipocyte size. LTs produced by adipocytes play an important role in attracting macrophages and T cells in in vitro chemotaxis assays. Mice that are deficient for the enzyme 5-lipoxygenase (5-LO), and therefore lack LTs, exhibit a decrease in HFD-induced AT macrophage and T-cell infiltration and are partially protected from HFD-induced insulin resistance. Similarly, treatment of HFD-fed wild-type mice with the 5-LO inhibitor Zileuton also results in a reduction of AT macrophages and T cells, accompanied by a decrease in insulin resistance. Together, these findings suggest that LTs represent a novel target in the prevention or treatment of obesity-associated inflammation and insulin resistance.
INSERM, U907, Nice, France.
Isabelle
I
Mothe-Satney
Chantal
C
Filloux
Hind
H
Amghar
Catherine
C
Pons
Virginie
V
Bourlier
Jean
J
Galitzky
Paul A
PA
Grimaldi
Chloé C
CC
Féral
Anne
A
Bouloumié
Emmanuel
E
Van Obberghen
Jaap G
JG
Neels
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency; D002460:Cell Line; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology*; D007333:Insulin Resistance / Q000502:physiology*; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications*; D050151:Subcutaneous Fat / Q000378:metabolism
D018925:Chemokines; D016207:Cytokines; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea