Interleukin-13 in Central Regulation of Metabolism

Interleukin-13 在代谢中枢调节中的作用

• 批准号: 10313463
• 负责人: Mayer Marc Chalom
• 金额: $ 4.16万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-08-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10313463
• 关键词: Adipocytes; Adipose tissue; Affect; Biogenesis; Body mass index; Brain; Brain region; Cell Nucleus; Cells; Cues; Cytokine Signaling; Data; Dopamine; Eating; Energy Metabolism; Enzymes; Exhibits; Fasting; Fatty acid glycerol esters; Food Energy; Gene Deletion; Gene Expression; Genetic Models; Genetic study; Glucose Intolerance; Helper-Inducer T-Lymphocyte; Hemorrhage; Homeostasis; Hormones; Human; Hyperphagia; Hypothalamic structure; IL13RA1 gene; Immune; Immune signaling; Immune system; Immunity; Infiltration; Inflammation Mediators; Inflammatory; Insulin Resistance; Interleukin-1 beta; Interleukin-13; Interleukin-4; Knock-out; Knowledge; LacZ Genes; Lead; Leptin; Lesion; Link; Liver; Lymphoid; Mediating; Membrane; Metabolic; Metabolic dysfunction; Metabolism; Midbrain structure; Modeling; Molecular; Mus; Muscle; NFKB Signaling Pathway; Nervous system structure; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organ; Overnutrition; Pathologic; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Population; Production; Receptor Gene; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stains; Substantia nigra structure; TNF gene; Testing; Thermogenesis; Tissues; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Weight Gain; blood glucose regulation; combat; cytokine; diabetes management; dopaminergic neuron; energy balance; food consumption; gain of function; genomic locus; glucose metabolism; insulin sensitivity; interleukin-13 receptor; loss of function; macrophage; metabolic phenotype; novel; pandemic disease; receptor; response

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.

项目摘要 免疫系统是代谢的重要和动态调节器。在外周组织中，营养过剩 和肥胖导致免疫细胞群的显著变化，引起信号传导的相关变化， 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 抵抗，II型免疫已被证明可以促进米色脂肪生物合成，葡萄糖稳态， 能量平衡。在大脑中，促炎性NF-kB信号通路的激活可导致 摄食过多和代谢功能障碍。II型免疫信号通路的激活是否可以恢复 能量平衡和防止肥胖尚未研究。IL-13是一种Th 2细胞因子， 通过其细胞受体IL-13 R β 1。Il 13 ra 1的全身缺失导致肥胖和血糖丢失 体内平衡IL 13 ra 1在黑质下和大脑腹侧被盖区表达。初步 数据显示，从多巴胺能中脑特异性缺失IL 13 ra 1至少部分地再现了 全身敲除的代谢表型。黑质和腹侧被盖区是大脑皮层的主要神经元。 中枢神经系统中多巴胺的主要生产者。许多研究都将中枢多巴胺活动与能量联系起来 平衡在这项研究中，我们将测试假设，中央IL-13信号通过其受体在 多巴胺能中脑维持能量平衡。我们将研究细胞和分子机制 它这样做的方式。我们将使用功能获得和功能丧失的遗传模型来测试我们的 假说.这项研究的知识有望填补我们对免疫系统如何 系统与神经系统相互作用，以协调代谢调节，并确定新的 中枢神经系统中调节能量平衡的途径。