RAGE/mDia1, Macrophage Trafficking and Inflammation in High Fat Feeding

 描述(申请人提供)：肥胖和胰岛素抵抗问题与2型糖尿病有关。糖尿病正在上升；缺乏完全有效的治疗方法。在……里面 从肥胖、胰岛素抵抗到糖尿病、严重的代谢障碍都与心血管疾病的风险增加有关。我们的目标是揭示巨噬细胞炎症影响高脂饮食和肥胖时代谢功能障碍的基本机制。我们的初步数据显示，在高脂肪喂养的小鼠中，年龄受体(RAGE)的配体在关键的代谢组织中甚至在弗兰克糖尿病发生之前就已经增加。我们的数据显示，RAGE的基因缺失可以显著预防高脂喂养引起的肥胖和胰岛素抵抗。重要的是，由于RAGE基因的缺失，脂肪组织巨噬细胞的蓄积、炎症极化和代谢特性大大降低。我们将阐述这样的假设，即巨噬细胞RAGE调节高脂肪喂养中的肥胖、肥胖和代谢功能障碍，这既是内在的，也是通过与脂肪细胞的相互作用来实现的。我们的项目将探索巨噬细胞炎症的四个关键特性，以发现高脂喂养中RAGE依赖的机制：单核细胞募集、巨噬细胞滞留和停滞、极化和代谢调节。最后，我们探讨了RAGE胞浆结构域与RAGE信号转导所需的Forin mDia1结合是如何导致高脂肪喂养中巨噬细胞功能障碍的。与人类受试者相关的转译研究将包括检查肥胖患者的脂肪组织巨噬细胞，以及在临床前模型中测试新型RAGE信号转导的小分子拮抗剂。

 DESCRIPTION (provided by applicant): The problems of obesity and insulin resistance have been linked to type 2 diabetes. Diabetes is on the rise; fully effective treatments are lacking. In the spectrum from obesity, insulin resistance, to diabetes, profound metabolic dysfunction is linked to increased risk for cardiovascular disease. Our goal is to uncover fundamental mechanisms by which macrophage inflammation impacts metabolic dysfunction in high fat feeding and obesity. Our preliminary data reveal that in high fat feeding in mice, ligands of the receptor for AGE (RAGE) are increased in key metabolic tissues even before the development of frank diabetes. Our data reveal that genetic deletion of RAGE results in significant protection against high fat feeding induced obesity and insulin resistance. Importantly, the accumulation, inflammatory polarization, and metabolic properties of adipose tissue macrophages are greatly reduced by deletion of RAGE. We will address the hypothesis that macrophage RAGE regulates obesity, adiposity and metabolic dysfunction in high fat feeding, both inherently and via cross-talk with the adipocyte. Our Project will explore four key properties of macrophage inflammation to discover RAGE-dependent mechanisms in high fat feeding: monocyte recruitment; macrophage retention and stasis; polarization; and metabolic regulation. Finally, we explore how the binding of the RAGE cytoplasmic domain to the formin, mDia1, which is required for RAGE signaling, contributes to macrophage dysfunction in high fat feeding. Translational studies relevant to human subjects will include examination of human adipose tissue macrophages in obesity and, in preclinical models, the testing of novel small molecule antagonists of RAGE signal transduction.