A new PPG application is proposed to identify and characterize gene networks in adipocytes and macrophages that influence insulin action. A combination of molecular, cellular, genetic and bioinformatics approaches will be used to define the components and behaviors of these networks at a genome-wide scale. The proposed studies will test the hypothesis that macrophage/adipocyte interactions result in altered programs of inflammatory gene expression in both cell types that contribute to insulin resistance. We will further test the hypothesis that PPARy agonists exert insulin-sensitizing effects by counter-regulating feed forward mechanisms that amplify inflammation within obese adipose tissue. Microarray and genome-wide location analysis will be performed to define the roles of NCoR/SMRT corepressor complexes as transcriptional checkpoints in PPARy-, NF-KB-, and AP-1-dependent gene expression and determine the importance of these complexes in mediating anti-inflammatory actions of PPARy agonists. Candidate genes identified by microarray studies and associated bioinformatics approaches will be tested for their pathophysiological roles in high fat diet-induced insulin resistance in mouse models. The results of these studies are likely to lead to new insights into the mechanisms underlying obesity-associated insulin resistance that can be exploited for development of novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK074868-04
Application #
7807958
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (J1))
Program Officer
Margolis, Ronald N
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$1,498,959
Indirect Cost
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
Riopel, Matthew; Seo, Jong Bae; Bandyopadhyay, Gautam K et al. (2018) Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function. J Clin Invest 128:1458-1470
Link, Verena M; Duttke, Sascha H; Chun, Hyun B et al. (2018) Analysis of Genetically Diverse Macrophages Reveals Local and Domain-wide Mechanisms that Control Transcription Factor Binding and Function. Cell 173:1796-1809.e17
Carlin, Aaron F; Vizcarra, Edward A; Branche, Emilie et al. (2018) Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages. Proc Natl Acad Sci U S A 115:E9172-E9181
Cardamone, Maria Dafne; Tanasa, Bogdan; Cederquist, Carly T et al. (2018) Mitochondrial Retrograde Signaling in Mammals Is Mediated by the Transcriptional Cofactor GPS2 via Direct Mitochondria-to-Nucleus Translocation. Mol Cell 69:757-772.e7
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
Oishi, Yumiko; Spann, Nathanael J; Link, Verena M et al. (2017) SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism. Cell Metab 25:412-427
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
Johnson, Andrew M F; Hou, Shaocong; Li, Pingping (2017) Inflammation and insulin resistance: New targets encourage new thinking: Galectin-3 and LTB4 are pro-inflammatory molecules that can be targeted to restore insulin sensitivity. Bioessays 39:
Li, Pingping; Liu, Shuainan; Lu, Min et al. (2016) Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance. Cell 167:973-984.e12
Eichenfield, Dawn Z; Troutman, Ty Dale; Link, Verena M et al. (2016) Tissue damage drives co-localization of NF-?B, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages. Elife 5:

Showing the most recent 10 out of 117 publications