12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice.
BACKGROUND
Recent understanding that insulin resistance is an inflammatory condition necessitates searching for genes that regulate inflammation in insulin sensitive tissues. 12/15-lipoxygenase (12/15LO) regulates the expression of proinflammatory cytokines and chemokines and is implicated in the early development of diet-induced atherosclerosis. Thus, we tested the hypothesis that 12/15LO is involved in the onset of high fat diet (HFD)-induced insulin resistance.


RESULTS
Cells over-expressing 12/15LO secreted two potent chemokines, MCP-1 and osteopontin, implicated in the development of insulin resistance. We assessed adipose tissue inflammation and whole body insulin resistance in wild type (WT) and 12/15LO knockout (KO) mice after 2-4 weeks on HFD. In adipose tissue from WT mice, HFD resulted in recruitment of CD11b(+), F4/80(+) macrophages and elevated protein levels of the inflammatory markers IL-1beta, IL-6, IL-10, IL-12, IFNgamma, Cxcl1 and TNFalpha. Remarkably, adipose tissue from HFD-fed 12/15LO KO mice was not infiltrated by macrophages and did not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. WT mice developed severe whole body (hepatic and skeletal muscle) insulin resistance after HFD, as measured by hyperinsulinemic euglycemic clamp. In contrast, 12/15LO KO mice exhibited no HFD-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output during clamp studies. Insulin-stimulated Akt phosphorylation in muscle tissue from HFD-fed mice was significantly greater in 12/15LO KO mice than in WT mice.


CONCLUSIONS
These results demonstrate that 12/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding.
Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, California, United States of America. dsears@ucsd.edu
Dorothy D
DD
Sears
Philip D
PD
Miles
Justin
J
Chapman
Jachelle M
JM
Ofrecio
Felicidad
F
Almazan
Divya
D
Thapar
Yury I
YI
Miller
D000273:Adipose Tissue / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism / Q000502:physiology*; D039481:CD11b Antigen / Q000096:biosynthesis; D003433:Crosses, Genetic; D004041:Dietary Fats / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D001616:beta-Galactosidase / Q000378:metabolism
C475064:12-15-lipoxygenase; D039481:CD11b Antigen; D004041:Dietary Fats; D007328:Insulin; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D001616:beta-Galactosidase