The surprising relationship between macrophages and insulin resistance provides a promising interface in which to apply our emerging understanding of the molecular mechanisms of nuclear receptor actions and recent progress in defining the underlying strategies of transrepression. In Project 2, we will focus on NCoR/SMRT corepressor complexes as transcriptional checkpoints controlling both ligand-dependent regulation of gene expression by nuclear receptors and the activities of signal-dependent transcription factors that drive inflammatory programs of gene expression. We will better define the molecular mechanisms and roles of the TBLi, TBLRi and GPS2 components of N-CoR corepressor complexes in the regulation of AP1/NF-kB target genes and we will use genome-wide location analyses (GWLA) to investigate the roles of these proteins in positive and negative regulation of macrophage and adipocyte gene expression.
Three Specific Aims are proposed.
Specific Aim i will test the hypothesis that N-CoR/SMRT complexes regulate inflammatory responses that contribute to insulin resistance and are targets of anti-diabetic actions of PPARy agonists. These studies will be performed in collaboration with Units i and 3 using mice reconstituted with N-CoR-/- or SMRT-/- fetal liver hematopoietic progenitor cells.
Specific Aim 2 will investigate the hypothesis that the TBLi/TBLRi exchange complex is regulated by signal-specific phosphorylation of TBLRi/TBLi. We will investigate the protein kinase control of corepressor complex dismissal from AP-1 and NF-kB target genes, and the role of these events in PPARy-mediated activation of positively regulated genes and transrepression of inflammatory response genes.
Specific Aim 3 will explore the role of GPS2 and KIAA1787 in JNK-dependent gene activation/repression events and to test the hypothesis that GPS2 is required for normal insulin sensitivity based on observations that JNK-expression and activity are consistently elevated in diet-induced obesity models and that AP-1 activity is constitutively increased on a subset of gene targets in N-CoR-/- macrophages. These studies will utilize a combination of single cell nuclear microinjection of siRNAs, an ultra-sensitive, multiplexed RNA quantification method (RASL) and ChlP-DASL to define roles of GPS2 in signal-dependent activation of inflammatory response genes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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University of California San Diego
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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:
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:
Thomas, Graham D; Hanna, Richard N; Vasudevan, Neelakatan T et al. (2016) Deleting an Nr4a1 Super-Enhancer Subdomain Ablates Ly6Clow Monocytes while Preserving Macrophage Gene Function. Immunity 45:975-987

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