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.
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.
|Franck, Niclas; Maris, Michael; Nalbandian, Sarah et al. (2014) Knock-down of IL-1Ra in obese mice decreases liver inflammation and improves insulin sensitivity. PLoS One 9:e107487|
|Lee, Yun Sok; Kim, Jung-whan; Osborne, Olivia et al. (2014) Increased adipocyte O2 consumption triggers HIF-1?, causing inflammation and insulin resistance in obesity. Cell 157:1339-52|
|Oh, Da Young; Walenta, Evelyn; Akiyama, Taro E et al. (2014) A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat Med 20:942-7|
|Bhargava, Vipul; Head, Steven R; Ordoukhanian, Phillip et al. (2014) Technical variations in low-input RNA-seq methodologies. Sci Rep 4:3678|
|Suh, Jae Myoung; Jonker, Johan W; Ahmadian, Maryam et al. (2014) Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513:436-9|
|McNelis, Joanne C; Olefsky, Jerrold M (2014) Macrophages, immunity, and metabolic disease. Immunity 41:36-48|
|Johnson, Andrew M F; Olefsky, Jerrold M (2013) The origins and drivers of insulin resistance. Cell 152:673-84|
|Dinasarapu, Ashok Reddy; Gupta, Shakti; Ram Maurya, Mano et al. (2013) A combined omics study on activated macrophages--enhanced role of STATs in apoptosis, immunity and lipid metabolism. Bioinformatics 29:2735-43|
|Bhargava, Vipul; Ko, Pang; Willems, Erik et al. (2013) Quantitative transcriptomics using designed primer-based amplification. Sci Rep 3:1740|
|Spann, Nathanael J; Glass, Christopher K (2013) Sterols and oxysterols in immune cell function. Nat Immunol 14:893-900|
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