12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet.
Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory damage triggered by stressors such as obesity and insulin resistance. We hypothesized that mice lacking 12-LO are protected against inflammatory-mediated damage associated with a "western" diet. To test this hypothesis, age-matched male 12-LO knockout (12-LOKO) and wild-type C57BL/6 (B6) mice were fed either a standard chow or western diet and assessed for several inflammatory markers. Western-fed B6 mice showed expected reductions in glucose and insulin tolerance compared with chow-fed mice. In contrast, western-fed 12-LOKO mice maintained glucose and insulin tolerance similar to chow-fed mice. Circulating proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-6, were increased in western B6 mice but not 12-LOKO mice, whereas the reported protective adipokine, adiponectin, was decreased only in western B6 mice. 12-LO activity was significantly elevated by western diet in islets from B6 mice. Islets from 12-LOKO mice did not show western-diet-induced islet hyperplasia or increases in caspase-3 apoptotic staining observed in western-fed B6 mice. Islets from 12-LOKO mice were also protected from reduced glucose-stimulated insulin secretion observed in islets from western-fed B6 mice. In visceral fat, macrophage numbers and monocyte chemoattractant protein-1 expression were elevated in western B6 mice but not 12-LOKO mice. These data suggest that 12-LO activation plays a role in western-diet-induced damage in visceral fat and islets. Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammation-mediated metabolic consequences of excess fat intake.
Nunemaker
Craig S
CS
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Chen
Meng
M
Pei
Hong
H
Kimble
Sarah D
SD
Keller
Susanna R
SR
Carter
Jeffrey D
JD
Yang
Zandong
Z
Smith
Kellie M
KM
Wu
Runpei
R
Bevard
Melissa H
MH
Garmey
James C
JC
Nadler
Jerry L
JL
D052438:Adipocytes, White / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052242:Adiponectin / Q000097:blood; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000097:blood; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000473:pathology*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000473:pathology*
D052242:Adiponectin; C499919:Adipoq protein, mouse; D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D001092:Arachidonate 12-Lipoxygenase; D005947:Glucose
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