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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053189-10
Application #
7638529
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
1998-08-12
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
10
Fiscal Year
2009
Total Cost
$298,060
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Jahansouz, C; Xu, H; Hertzel, A V et al. (2018) Partitioning of adipose lipid metabolism by altered expression and function of PPAR isoforms after bariatric surgery. Int J Obes (Lond) 42:139-146
Duffy, Cayla M; Xu, Hongliang; Nixon, Joshua P et al. (2017) Identification of a fatty acid binding protein4-UCP2 axis regulating microglial mediated neuroinflammation. Mol Cell Neurosci 80:52-57
Hertzel, Ann V; Xu, Hongliang; Downey, Michael et al. (2017) Fatty acid binding protein 4/aP2-dependent BLT1R expression and signaling. J Lipid Res 58:1354-1361
Steen, Kaylee A; Xu, Hongliang; Bernlohr, David A (2017) FABP4/aP2 Regulates Macrophage Redox Signaling and Inflammasome Activation via Control of UCP2. Mol Cell Biol 37:
Xu, Hongliang; Hertzel, Ann V; Steen, Kaylee A et al. (2016) Loss of Fatty Acid Binding Protein 4/aP2 Reduces Macrophage Inflammation Through Activation of SIRT3. Mol Endocrinol 30:325-34
Hotamisligil, Gökhan S; Bernlohr, David A (2015) Metabolic functions of FABPs--mechanisms and therapeutic implications. Nat Rev Endocrinol 11:592-605
Jahansouz, Cyrus; Serrot, Federico J; Frohnert, Brigitte I et al. (2015) Roux-en-Y Gastric Bypass Acutely Decreases Protein Carbonylation and Increases Expression of Mitochondrial Biogenesis Genes in Subcutaneous Adipose Tissue. Obes Surg 25:2376-85
Ali, Asem H; Mundi, Manpreet; Koutsari, Christina et al. (2015) Adipose Tissue Free Fatty Acid Storage In Vivo: Effects of Insulin Versus Niacin as a Control for Suppression of Lipolysis. Diabetes 64:2828-35
Xu, Hongliang; Hertzel, Ann V; Steen, Kaylee A et al. (2015) Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2. Mol Cell Biol 35:1055-65
Frohnert, Brigitte I; Bernlohr, David A (2014) Glutathionylated products of lipid peroxidation: A novel mechanism of adipocyte to macrophage signaling. Adipocyte 3:224-9

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