Molecular and physiological studies have revealed that inflammation of adipose tissue is a key determinant in the development of the metabolic syndrome and a variety of animal models have been utilized to identify mechanisms that link adipocytes and macrophages to disease. Of these, the Fatty Acid Binding Protein 4 (FABP4, also known as aP2) loss/gain mouse has been particularly insightful in developing our current understanding of inflammation, ER stress, mitochondrial dysfunction and metabolic disease. Fatty acid binding proteins are intracellular FFA chaperones found expressed at high levels in adipocytes and macrophages. Surprisingly, when placed on high fat diets, FABP4 knockout mice exhibit attenuated characteristics of the metabolic syndrome including diminished lipolysis, reduced TNF? and increased adiponectin expression, improved insulin sensitivity, decreased NF-?B activation, protection from asthma, diminished atherogenic capacity and attenuate neuroinflammation. In contrast, mice over-expressing FABP in adipose tissue exhibit potentiated characteristics of the metabolic syndrome including increased lipolysis, exacerbated insulin resistance, decreased adiponectin secretion, and mild cardiac hypertrophy. Similar to the animal models, humans with decreased adipocyte FABP (arising via a polymorphism in the FABP4/aP2 promoter) exhibit reduced risk for hypertriglyceridemia, type 2 diabetes and cardiovascular disease. During the last funding cycle the laboratory has identified a novel FABP4-SirT1-UCP2 axis that regulates lipid metabolism in macrophages and adipocytes. Briefly, molecular, genetic or pharmacologic loss of FABP leads to increased cellular fatty acids and a cascade of events linked to SirT1 activation and the up regulation of UCP2. Increased expression of UCP2 enables increased ?-oxidation of FFA, attenuates pyruvate entry into the mitochondrion, reduces the level of reactive oxygen species and oxidative stress. Diminished ROS reduces mitochondrial protein oxidation, the mitochondrial Unfolded Protein Response (mtUPR), activation of NF-?B signaling, and induction of the inflammasome. The central hypothesis for this application is that the FABP4-FFA equilibrium controls activation of SirT1 and subsequently UCP2 expression in macrophages. Moreover, up regulation of UCP2 is both necessary and sufficient to shift immune cells of high fat fed mice from a classically activated pro-inflammatory M1 phenotype to the alternatively activated anti-inflammatory M2 form. To test this hypothesis, the following specific aims are proposed:
Aim 1. Evaluate the regulation of SirT1 by fatty acids and its control by FABP4.
Aim 2. Examine cellular metabolism and polarization of cultured macrophages stably overexpressing UCP2.
Aim 3. Evaluate the metabolic effects of macrophage-specific knockout and overexpression of UCP2 in experimental mice.

Public Health Relevance

This application is aimed at understanding the role that Uncoupling Protein 2 may play in regulating inflammation and metabolic disease. Moreover, the work will establish that intracellular fatty acids, particularly monounsaturated fatty acids, are potential bioregulators of inflammation and represent an untapped therapeutic potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053189-19
Application #
9924511
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
1998-08-12
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
19
Fiscal Year
2020
Total Cost
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
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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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