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.
|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|
Showing the most recent 10 out of 108 publications