The metabolic syndrome links accumulation of visceral adipose tissue to hyperlipidemia, impaired insulin sensitivity, susceptibility to thrombosis, inflammation, and impaired endothelial function resulting in increased risk for type 2 diabetes, cardiovascular disease and hypertension. A variety of molecular and physiological studies have identified intracellular free fatty acids (FFA) as key metabolites, linking lipid metabolism to signal transduction, insulin resistance, inflammation and adipocytokine production. Fatty acid binding proteins (FABP) are intracellular FFA receptors found expressed to high levels in adipocytes and macrophages. Adipocytes express high levels of Adipocyte FABP (AFABP/aP2) and low levels of Epithelial FABP (EFABP/mal1). In contrast, macrophages express higher levels of EFABP/mal1 and low levels of AFABP/aP2. When placed on high fat diets, FABP knockout mice (devoid of either AFABP/aP2 or EFABP/mal1) exhibit attenuated characteristics of the metabolic syndrome including reduced TNF alpha and increased adiponectin expression, improved insulin sensitivity, decreased NF-kB activation and atherogenic potential. In contrast, mice overexpressing FABP in adipose tissue exhibit potentiated characteristics of the metabolic syndrome included exacerbated insulin resistance, decreased adiponectin secretion, and accumulation of lipids in cardiac tissue. The focus of this application is on the mechanistic basis for how changes in the FABP level within the cell leads to attenuated or potentiated characteristics of the metabolic syndrome. We hypothesize that FABPs serve as intracellular receptors that function as sensors for FFA and mediate inflammatory and hormonal signaling pathways dysregulated in obesity linked insulin resistance. Such regulation is mediated via protein-protein interactions between holo-FABPs (ligand bound forms) and target proteins including JAK2 and IKK beta. To test this hypothesis we propose to: A. Determine the structural parameters defining the FABP-target protein interactions. B. Assess the functional significance of the FABP-target protein interactions on signal transduction and metabolic process in adipocytes and macrophages. C. Evaluate the role of FABP-target protein interaction in vivo using transgenic mice.
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