This project, which has been continuously funded for 30 years, addresses adipose metabolism that controls whole body glucose and lipid homeostasis in health and disease. Co-morbidities associated with obesity, including insulin resistance and type 2 diabetes, can result from insufficient deposition and storage of triglyceride (TG) within adipose tissue, leading to deleterious effects on liver, skeletal muscle, cardiovascular organs and insulin secreting beta cells. Thus a high capacity of adipose tissue for fatty acid esterification and sequestration of TG is vital during caloric surplus. However, thi function of adipocytes involves complex and incompletely understood interactions with macrophages and other cells of the immune system that infiltrate adipose tissue in obesity. Three key mechanistic questions are: What are the major signaling pathways that regulate fatty acid esterification and TG sequestration in adipocytes? How do macrophages modulate these pathways of adipocyte lipid storage? What controls macrophage infiltration into adipose tissue? This project previously employed siRNA screens to discover the Ste20 ortholog Map4k4, a protein kinase we discovered is integral to all three questions. Based on our recent exciting data, we now hypothesize that 1. Map4k4 in adipocytes, activated by macrophage cytokines, markedly suppresses adipocyte fatty acid esterification and TG sequestration, 2. Knockout of Map4k4 in adipocytes in mice will enhance TG storage in adipose tissue and increase glucose tolerance and decrease fatty liver, and 3. Map4k4 in adipose endothelial cells mediates upregulation of adhesion molecules that promote macrophage extravasation. We propose to identify and define the Map4k4 signaling pathways for lipogenic suppression in adipocytes in vitro (Aim 1) and in vivo (Aim 2) and for activation of endothelial cell permeability (Aim 3). We will define the specific roles of PPARg, SREBP1c and ChREBP as targets of Map4k4 regulation in adipocytes, and utilize two floxed mouse models we already generated wherein Map4k4 is selectively silenced (shRNA) or ablated in adipocytes or endothelial cells, respectively. We will test whether increased lipogenesis in adipose specific Map4k4 KO mice results in increased glucose tolerance, and whether adhesion molecule expression and macrophage extravasation is inhibited in endothelial specific KO mice. These experiments will provide important insights into adipose lipid handling in metabolic regulation and Map4k4 signaling in cross talk among cell types within adipose tissue.

Public Health Relevance

Obesity is known to greatly increase the risk of developing diabetes, but the reasons for this association are incompletely understood. It has recently become clear that the normal functions of fat tissue seem to be compromised in individuals who go on to develop diabetes and we wish to understand why this occurs. We are using animal models to understand the complex interactions between fat cells, cells of the immune system, and cells that make up blood vessels, and how these interactions may contribute to normal function of fat tissue, as well as defects that may lead to diseases like diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK030898-31
Application #
8688992
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
1981-09-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
31
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655
Virbasius, Joseph V; Czech, Michael P (2016) Map4k4 Signaling Nodes in Metabolic and Cardiovascular Diseases. Trends Endocrinol Metab 27:484-92
Fitzgibbons, Timothy P; Czech, Michael P (2016) Emerging evidence for beneficial macrophage functions in atherosclerosis and obesity-induced insulin resistance. J Mol Med (Berl) 94:267-75
Senol-Cosar, Ozlem; Flach, Rachel J Roth; DiStefano, Marina et al. (2016) Tenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissue expansion. Nat Commun 7:10686
Roth Flach, Rachel J; Danai, Laura V; DiStefano, Marina T et al. (2016) Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia. J Biol Chem 291:16221-30
Cohen, Jessica L; Shen, Yuefei; Aouadi, Myriam et al. (2016) Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA. Mol Pharm 13:964-78
Roth Flach, Rachel J; Guo, Chang-An; Danai, Laura V et al. (2016) Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function. Mol Cell Biol 36:1740-9
Roth Flach, Rachel J; Skoura, Athanasia; Matevossian, Anouch et al. (2015) Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis. Nat Commun 6:8995
Roth Flach, Rachel J; Czech, Michael P (2015) NETs and traps delay wound healing in diabetes. Trends Endocrinol Metab 26:451-2
Tencerova, Michaela; Aouadi, Myriam; Vangala, Pranitha et al. (2015) Activated Kupffer cells inhibit insulin sensitivity in obese mice. FASEB J 29:2959-69
Pedersen, David J; Guilherme, Adilson; Danai, Laura V et al. (2015) A major role of insulin in promoting obesity-associated adipose tissue inflammation. Mol Metab 4:507-18

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