Obesity is characterized by increased basal lipolysis and circulating free fatty acids that in turn potentiate hepatic glucose output and affect 2-cell glucose stimulated insulin secretion. In many, but not all individuals, obesity is also associated with chronic low-grade inflammation that underlies insulin resistance at the adipocyte and contributes to the eventual development type II diabetes. However, the mechanisms by which increased free fatty acid contribute to inflammation and insulin resistance are complex and multifactoral. In adipose tissue, adipocyte derived fatty acids bind to TLR4 and other free fatty acid receptors on the macrophage cell surface eventually leading to NF-kB-dependent pro-inflammatory cytokine production. Much of adipocyte and macrophage intracellular fatty acid metabolism is mediated by cytoplasmic fatty acid binding proteins (FABPs). A key function of FABP is transport of fatty acid metabolites such as prostaglandins and leukotrienes. Recent published and unpublished work from our laboratory has shown that FABP play a major and profound role in leukotriene A4 (LTA4) metabolism. LTA4 is formed by liberation of arachidonic acid from phospholipid membranes and subsequent metabolism by 5-lipoxygenase and 5-lipoxygenase activating protein. By virtue of the unstable epoxide linkage LTA4 is rapidly hydrolyzed in water (t1/2 ~ 3 seconds) to biologically inert molecules. In contrast, when bound to FABP the half-life of LTA4 increases to ~20 minutes-- a 400- fold increase in stability. LTA4 is a necessary intermediate to production of leukotriene B4 and cysteinyl leukotrienes such as leukotriene C4 (LTC4). Leukotrienes are important mediators of inflammation and chemotaxis of immune cells such as macrophages and T cells. Consistent with this, cell lines from FABP null macrophages exhibit markedly reduced LTC4 biosynthesis and an anti- inflammatory gene expression profile. These results are consistent with the phenotype of the FABP null mice. High fat fed or genetically obese FABP4 null mice exhibit protection from development of insulin resistance or atherogenesis and small molecule inhibitors of FABP reduce inflammatory cytokine production in macrophages. The goal of the proposed study is to test the hypothesis that obesity-linked inflammation is mediated, in part, via the macrophage derived biosynthesis of cysteinyl leukotrienes and subsequent downstream signaling to activate NF-kB-dependent production of inflammatory cytokines. This study will increase understanding of the mechanisms by which obesity leads to inflammation and may be useful in determination of methods of prevention and treatment of obesity-induced inflammation and insulin resistance by targeting inflammatory eicosanoid biology.
The proposed course of study will increase understanding of the mechanisms by which inflammation occurs in macrophages. This understanding can provide insights into how inflammation contributes to disease states such as type II diabetes and allow for exploration of new therapeutic avenues or the re-purposing of existing therapies, to combat these diseases.
|Frohnert, Brigitte I; Long, Eric K; Hahn, Wendy S et al. (2014) Glutathionylated lipid aldehydes are products of adipocyte oxidative stress and activators of macrophage inflammation. Diabetes 63:89-100|
|Long, Eric K; Olson, Dalay M; Bernlohr, David A (2013) High-fat diet induces changes in adipose tissue trans-4-oxo-2-nonenal and trans-4-hydroxy-2-nonenal levels in a depot-specific manner. Free Radic Biol Med 63:390-8|
|Long, Eric K a; Hellberg, Kristina; Foncea, Rocio et al. (2013) Fatty acids induce leukotriene C4 synthesis in macrophages in a fatty acid binding protein-dependent manner. Biochim Biophys Acta 1831:1199-207|