The molecular mechanisms linking obesity, insulin resistance, diabetes, cardiovascular diseases and other associated pathologies are not fully understood. In the past decade, studies in many groups, including ours, have illustrated the importance of inflammation in metabolic disease, particularly in obese adipose tissue. Macrophages and their interactions with adipocytes in the adipose tissue are potentially involved in this process in this process through the integration of lipid signals with inflammatory networks. In this project, we propose to focus on the function and mechanisms of action of fatty acid binding proteins (FABPs) that integrate macrophage and adipocyte function and significantly contribute to metabolic diseases associated with obesity. Adipocyte/macrophage FABPs, aP2 and mal1, coordinately regulate adipocyte and macrophage responses and mice with targeted mutations in these genes exhibit marked protection against insulin resistance, type 2 diabetes, fatty liver disease, atherosclerosis, and asthma. Recently, our lab and other groups demonstrated that aP2 function is highly relevant to human disease by discovering the links between genetic variation at aP2 locus and the risk for type 2 diabetes and cardiovascular disease. New and exciting emerging data both in our group and elsewhere also demonstrated that aP2 is secreted from adipocytes and systemic aP2 levels are strongly associated with obesity, type 2 diabetes and cardiovascular disease in humans. Furthermore, these FABPs regulate the secretion of additional proteins from the adipose tissue and play a significant role in mediating lipotoxic responses in target cells, including macrophages. In the studies planned in this proposal, we will address the biological functions of the soluble FABP, focusing primarily on aP2, characterize other FABP-regulated secreted products in adipose tissue and explore the molecular mechanisms by which aP2 mediate lipotoxicity, with a focus on lipid-induced endoplasmic reticulum stress and related signaling and transcriptional networks. In these studies we will also utilize a newly developed chemical tool to inhibit aP2 which can mimic the metabolic consequences of genetic deficiency of FABPs in cells and in whole animals. Studying the biology and mechanisms of action of adipocyte/macrophage FABPs will be insightful in building models to understand how metabolic disease cluster around obesity and mechanistically linked to each other and carry this knowledge to human disease for preventive and therapeutic applications.

Public Health Relevance

Studying the biology and mechanisms of action of adipocyte/macrophage FABPs will be insightful in building models to understand how metabolic disease cluster around obesity and mechanistically link to each other and carry this knowledge to human disease for unique preventative and therapeutic opportunities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064360-08
Application #
8212428
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2003-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$380,711
Indirect Cost
$147,860
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Ertunc, Meric Erikci; Sikkeland, Jørgen; Fenaroli, Federico et al. (2015) Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity. J Lipid Res 56:423-34
Arruda, Ana Paula; Hotamisligil, Gökhan S (2015) Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes. Cell Metab 22:381-97
Hotamisligil, Gökhan S; Bernlohr, David A (2015) Metabolic functions of FABPs--mechanisms and therapeutic implications. Nat Rev Endocrinol 11:592-605
Syamsunarno, Mas Rizky A A; Iso, Tatsuya; Hanaoka, Hirofumi et al. (2013) A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting. PLoS One 8:e79386
Iso, Tatsuya; Maeda, Kazuhisa; Hanaoka, Hirofumi et al. (2013) Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle. Arterioscler Thromb Vasc Biol 33:2549-57
Cao, Haiming; Sekiya, Motohiro; Ertunc, Meric Erikci et al. (2013) Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab 17:768-78
Ghelfi, Elisa; Yu, Chen-Wei; Elmasri, Harun et al. (2013) Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma. Am J Pathol 182:1425-33
Babaev, Vladimir R; Runner, Robert P; Fan, Daping et al. (2011) Macrophage Mal1 deficiency suppresses atherosclerosis in low-density lipoprotein receptor-null mice by activating peroxisome proliferator-activated receptor-γ-regulated genes. Arterioscler Thromb Vasc Biol 31:1283-90
Nieman, Kristin M; Kenny, Hilary A; Penicka, Carla V et al. (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17:1498-503
Yecies, Jessica L; Zhang, Hui H; Menon, Suchithra et al. (2011) Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 14:21-32

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