We propose an ambitious program of collaborative research to identify and characterize molecular mechanisms responsible for altered programs of inflammatory gene expression that contribute to insulin resistance. We will capitalize on our recent discoveries of unexpected roles of GPS2 and the nuclear receptor co-repressors NCoR and SMRT in regulation of inflammatory signaling pathways in macrophages and adipocytes. We will extend studies of novel mechanisms mediating the recruitment of pro-inflammatory macrophages into adipose tissue that have clear translational potential. We will utilize newly developed technologies to characterize the genomic locations and functions of PPARy in adipose tissue macrophages in vivo to determine mechanisms by which macrophage PPARy contributes to insulin-sensitizing functions of thiazolidinediones. We will investigate the roles o 3 dimensional chromatin interactions and non-coding RNAs in positive and negative regulation of inflammatory gene expression. Overall, the proposed studies are expected to lead to new insights into mechanisms underlying obesity-associated insulin resistance that will facilitate development of new approaches for the prevention and treatment of type 2 diabetes.

Public Health Relevance

The proposed studies will significantly advance our understanding of mechanisms that regulate the initiation, amplification and resolution of pathogenic forms of inflammation that contribute to insulin resistance and the development of type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK074868-06
Application #
8269179
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J1))
Program Officer
Margolis, Ronald N
Project Start
2006-04-01
Project End
2017-04-30
Budget Start
2012-05-25
Budget End
2013-04-30
Support Year
6
Fiscal Year
2012
Total Cost
$1,765,823
Indirect Cost
$625,970
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Fernandez, Marina O; Sharma, Shweta; Kim, Sun et al. (2017) Obese Neuronal PPAR? Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility. Endocrinology 158:121-133
Ying, Wei; Wollam, Joshua; Ofrecio, Jachelle M et al. (2017) Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling. J Clin Invest 127:1019-1030
Li, Pingping; Liu, Shuainan; Lu, Min et al. (2016) Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance. Cell 167:973-984.e12
Oh, Da Young; Olefsky, Jerrold M (2016) G protein-coupled receptors as targets for anti-diabetic therapeutics. Nat Rev Drug Discov 15:161-72
Baeza-Raja, Bernat; Sachs, Benjamin D; Li, Pingping et al. (2016) p75 Neurotrophin Receptor Regulates Energy Balance in Obesity. Cell Rep 14:255-68
Glass, Christopher K; Natoli, Gioacchino (2016) Molecular control of activation and priming in macrophages. Nat Immunol 17:26-33
McNelis, Joanne C; Lee, Yun Sok; Mayoral, Rafael et al. (2015) GPR43 Potentiates ?-Cell Function in Obesity. Diabetes 64:3203-17
Link, Verena M; Gosselin, David; Glass, Christopher K (2015) Mechanisms Underlying the Selection and Function of Macrophage-Specific Enhancers. Cold Spring Harb Symp Quant Biol 80:213-21
Li, Pingping; Oh, Da Young; Bandyopadhyay, Gautam et al. (2015) LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat Med 21:239-247
Gorden, D Lee; Myers, David S; Ivanova, Pavlina T et al. (2015) Biomarkers of NAFLD progression: a lipidomics approach to an epidemic. J Lipid Res 56:722-36

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