Chronic tissue inflammation is an important contributor to the decreased insulin sensitivity associated with obesity/type 2 diabetes and that the macrophage adipocyte axis is a key effector causing this metabolic defect. We have recentiy taken a new approach to this problem and have generated adipocyte-specific NCoR KO mice (AKO mice). In AKO animals, PPARy becomes constitutively active, leading to a robust anti- inflammatory insulin sensitive phenotype. We also find that phosphorylation of PPARy at serine 273 is markedly blunted when NCoR is deleted in adipocytes. In this application, we propose several new hypotheses to explain the insulin sensitivity in our AKO mice and these lead to a number of studies to examine the regulation of serine 273 serine PPARy phosphorylation and the functional propoerties of this non-phosphorylated form of the receptor. We will also conduct a series of molecular studies to identity the global gene expression patterns in primary adipocytes from WT and AKO mice, as well as the global DNA binding sites (cistromes) of PPARy, NCoR and SMRT. We also hypothesize that the central physiologic mechanism leading to the insulin resistance in the AKO mice is that deletion of NCoR leads to cell autonomous activation of PPARy. Thus, causes reduced chemotactic signaling, with decreased adipose tissue macrophage content, decreased inflammation and improved insulin sensitivity. In this context, we have made new observations indicating that the leukotriene chemokine, LBT4, and its receptor BLT1, may play a dominant role in macrophage migration into adipose tissue. Thus, we have compelling new data showing that treatment of macrophages with a BLT1 inhibitor markedly reduces macrophage chemotaxis in vitro and, that treatment of obese mice with the BLT1 inhibitor causes a robust improvement in glucose tolerance and insulin sensitivity. A combined in vitro and in vivo approach is proposed to test the hypotheses generated from these new data. These latter studies have strong translational implications since BLT1 could emerge as an important new target for insulin sensitizing drug discovery.

Public Health Relevance

The proposed studies will directly contribute to our understanding of mechanisms that regulate the initiation, amplification and resolution of pathogenic forms of inflammation that contribute 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 #
4P01DK074868-10
Application #
9041573
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
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