Interleukin-13 in Central Regulation of Metabolism

项目总结 免疫系统是新陈代谢的重要和动态调节器。在外周组织中，营养过剩 肥胖导致免疫细胞数量的显著变化，导致相关的信号和 组织功能。而I型免疫与促炎细胞因子和胰岛素的释放有关 耐药，II型免疫已被证明促进米色脂肪的生物合成，葡萄糖稳态，以及 能量平衡。在大脑中，促炎因子-kB信号通路的激活可以导致 吞噬过多和代谢功能障碍。II型免疫信号通路的激活能否恢复 能量平衡和预防肥胖还没有被研究过。IL-13是一种Th2细胞因子 通过其细胞受体IL-13R1.IL13ra1全身缺失导致肥胖和血糖下降 动态平衡。IL13ra1在黑质和大脑腹侧被盖区表达。初步 数据显示，多巴胺能中脑中IL13ra1的特异性缺失至少部分地复制了 全身击倒的代谢表型。黑质和腹侧被盖区是 中枢神经系统中多巴胺的主要生产者。许多研究已经将中枢多巴胺活动与能量联系起来。 平衡。在这项研究中，我们将检验这一假设，即中枢IL-13通过其受体在 多巴胺能中脑以维持能量平衡。我们将研究细胞和分子机制。 它通过这种方式做到了这一点。我们将同时使用功能获得和功能丧失遗传模型来测试我们的 假设。这项研究的知识有望填补我们对免疫系统如何免疫的主要空白 系统与神经系统相互作用以协调新陈代谢调节，并识别新的 中枢神经系统中调节能量平衡的通路。

PROJECT SUMMARY The immune system is an important and dynamic regulator of metabolism. In peripheral tissues, over-nutrition and obesity lead to marked changes in immune cell population, causing associated shifts in signaling and tissue function. While type I immunity is associated with the release of pro-inflammatory cytokines and insulin resistance, type II immunity has been shown to promote beige fat biogenesis, glucose homeostasis, and energy balance. In the brain, activation of the pro-inflammatory NF-kB signaling pathway can lead to hyperphagia and metabolic dysfunction. Whether activation of type II immune signaling pathways can restore energy balance and protect against obesity has not yet been investigated. IL-13 is a Th2 cytokine that signals through its cellular receptor IL-13R1. Whole body deletion of Il13ra1 causes obesity and loss of blood glucose homeostasis. Il13ra1 is expressed in the subtantia nigra and ventral tegmental area of the brain. Preliminary data show that specific deletion of Il13ra1 from the dopaminergic midbrain at least partially reproduces the metabolic phenotypes of the whole-body knockout. The substantia nigra and ventral tegmental area are the primary producers of dopamine in the CNS. Numerous studies have related central dopamine activity to energy balance. In this study, we will test the hypothesis that central IL-13 signals through its receptor in the dopaminergic midbrain to maintain energy balance. We will investigate the cellular and molecular mechanisms by which it does so. We will use both gain-of-function and loss-of-function genetic models to test our hypothesis. Knowledge from this study is expected to fill major gaps in our understanding of how the immune system interacts with the nervous system to coordinate metabolic regulation, and also to identify novel pathways in the CNS that modulate energy balance.