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 TNFα and increased adiponectin expression, improved insulin sensitivity, decreased NF-κB 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 PPARγ. Moreover, LTE4 treatment of adipocytes results in activation of MAPK pathway, phosphorylation of p38 and JNK and decreased glucose transport. These findings lead to the hypothesis that: adipocyte derived saturated and n6 fatty acids bind to receptors on resident macrophages resulting in a sustained increase in cytoplasmic calcium, activation of the cPLA2/5-lipoxygenase pathway and fatty acid binding protein-dependent leukotriene synthesis. Macrophage-derived LTA4 is metabolized to LTB4 while cysteinyl leukotrienes lead to the activation of NF-κB and 1) the M2 to M1 polarization transition in macrophages and 2) impaired insulin signaling and altered adipokine secretion in adipocytes. To test this hypothesis, we propose the following 4 aims: 1. Profile the abundance of eicosanoids in animal models of obesity and insulin resistance. 2. Evaluate the effect of saturated and n6 fatty acids to regulate calcium flux, cPLA2/5-LO membrane translocation and eicosanoid biosynthesis in macrophages. 3. Assess the role of fatty acid binding proteins in leukotriene biosynthesis. 4. Examine the effect of leukotrienes on adipocyte and macrophage signal transduction and metabolism.
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 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 of insulin resistance.
Showing the most recent 10 out of 12 publications
