Fatty acid binding proteins (FABPS) are intracellular free fatty acid receptors found expressed at high levels in adipocytes and macrophages. FABPs bind a variety of unesterified fatty acids and other lipid second messengers and mediate their intracellular metabolism. When placed on high fat diets, FABP knockout mice exhibit attenuated characteristics of the metabolic syndrome including diminished adipocyte lipolysis, reduced TNF? and increased adiponectin expression, improved insulin sensitivity, decreased NF-?B activation, protection from asthma and diminished atherogenic capacity. In contrast, mice over-expressing FABP in adipose tissue exhibit potentiated characteristics of the metabolic syndrome included increased lipolysis, exacerbated insulin resistance, decreased adiponectin secretion, and mild cardiac hypertrophy. Humans with decreased adipocyte FABP (arising via a polymorphism in the AFABP/aP2 promoter) exhibit reduced risk for hypertriglyceridemia, type 2 diabetes and cardiovascular disease. In work carried out under NIH DK053189 we have demonstrated that the FABPs of adipose tissue are required for inflammatory leukotriene biosynthesis. Since LTA4 is a precursor to the monocyte recruitment factor LTB4 and the inflammatory cysteinyl leukotrienes (LTC4, LTD4 and LTE4), adipose tissue from FABP null mice and FABP null macrophage cell lines exhibit reduced levels of inflammatory eicosanoids. Treatment of macrophages with leukotrienes results in an increase in iNOS and MCP1 expression while decreasing PPAR?. Moreover, LTC4 treatment of adipocytes results in decreased phosphorylation of Akt and attenuated glucose transport while increasing basal and forskolin-stimulated lipolysis. These findings lead to the hypothesis that: fatty acids, either fro diet or from adipocyte lipolysis, stimulate resident macrophages resulting in fatty acid binding protein-dependent leukotriene synthesis. LTB4 and LTC4 promote inflammatory gene expression and cytokine secretion by macrophages, and LTC4 impairs insulin signaling, alters adipokine secretion and increases lipolysis in adipocytes. To test this hypothesis, we propose the following four specific aims: 1. Determine the role of fatty acids and fatty acid binding proteins in macrophage leukotriene biosynthesis using cell culture models. 2. Assess the role of fatty acids and fatty acid binding proteins in adipose tissue leukotriene biosynthesis using animal models. 3. Evaluate the interaction of FABPs with LTA4 and LTA4 metabolizing enzymes. 4. Examine the effects of leukotrienes on macrophage and adipocyte signal transduction and cytokine synthesis.
Inflammation is a common theme in a variety of metabolic disease states including diabetes, asthma and allergy. Work detailed in this application describes the analysis of fatty acid binding protein dependent production of inflammatory lipids in adipose tissue and tests the hypothesis that leukotrienes play a prominent role in the development of insulin resistance. The studies in sum open new avenues into the biology of adipose tissue, the role(s) of inflammatory lipids in mediating the development of insulin resistance and identification of new sites for molecular therapies.
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