1215-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice1215 -脂氧合酶是必需的早发性高脂肪食源性脂肪组织炎症和胰岛素抵抗在老鼠身上.pdf

12/15-Lipoxygenase Is Required for the Early Onset of High Fat Diet-Induced Adipose Tissue Inflammation and Insulin Resistance in Mice 1 1 2 1 1 Dorothy D. Sears *, Philip D. Miles , Justin Chapman , Jachelle M. Ofrecio , Felicidad Almazan , Divya Thapar1, Yury I. Miller1 1 Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, California, United States of America, 2 Pfizer Inc., La Jolla, California, United States of America Abstract 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. Methodology/Principal Findings: 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-1b, IL-6, IL-10, IL-12, IFNc, Cxcl1 and TNFa. 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 m