Effects of maternal insulin resistance on hypothalamic feeding circuit in progeny

母体胰岛素抵抗对后代下丘脑喂养回路的影响

• 批准号: 7682951
• 负责人: STEPHANIE Louise PADILLA
• 金额: $ 4.12万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682951
• 关键词: Address; Affect; Alleles; Animal Husbandry; Animals; Axon; Biological Models; Body Composition; Body Weight; Brain; Breeding; Cell Nucleus; Data; Development; Developmental Process; Diabetes Mellitus; Diet; Discipline of Nursing; Energy Metabolism; Environment; Event; Fatty acid glycerol esters; Female; Growth; Homeostasis; Hormonal; Human; Hypothalamic structure; Incidence; Ingestion; Insulin; Insulin Receptor; Insulin Resistance; Label; Laboratories; Lead; Metabolic; Modeling; Molecular; Neuronal Differentiation; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Phenotype; Population; Predisposition; Pregnancy; Prevention strategy; Secondary to; Signal Transduction; Structure of nucleus infundibularis hypothalami; Testing; Time; Transgenic Mice; Transgenic Organisms; design; feeding; fetal; insight; male; member; mouse model; neural circuit; neuronal cell body; novel strategies; obesity in children; obesity prevention; offspring; postnatal; research study; weight maintenance

We hypothesize that maternal insulin resistance (obesity) influences fetal and/or early postnatal development of hypothalamus to promote obesity and type 2 diabetes (T2DM) in progeny. Such an effect could contribute to the accelerating incidence of obesity and T2DM currently being encountered worldwide. We will develop a mouse model to investigate this issue using genetically imposed maternal insulin resistance as a surrogate for obesity. In preliminary studies, we find that maternal insulin resistance affects adiposity and insulin homeostasis in progeny. The Specific Aims of this project are: 1) to use this mouse model to assess effects of maternal insulin resistance- and interactions with maternal high fat diet- on body composition and energy and insulin homeostasis of progeny; and 2) to examine the molecular/developmental mechanisms through which such maternal insulin resistance influences the development of hypothalamic feeding circuits. We will perform a comprehensive analysis of the consequences of maternal insulin resistance on energy and insulin homeostasis in the progeny and extend the analysis of our model to consider the effects of fat content of the maternal diet. We will assess the effects of maternal insulin resistance on developmental processes in the hypothalamus, initially focusing on the arcuate nucleus. The effects of maternal insulin resistance on the development of the arcuate nucleus will be assessed by quantitative analyses of the cell bodies of three functionally distinct arcuate neuronal populations (POMC, NPY and RIP neurons) and their axonal projections to secondary targets in the hypothalamus. Defining the time window and mechanisms of susceptibility to gestational and early extrauterine effects on the progeny of maternal insulin resistance should provide important insights into the corresponding window of susceptibility in humans. In the longer term, defining the relevant maternal signals influencing molecular events in the developing brain could lead to the design of novel strategies for prevention of obesity/T2DM in humans.

我们假设母体胰岛素抵抗（肥胖）会影响胎儿和/或早期产后 下丘脑的发展以促进后代的肥胖和2型糖尿病（T2DM）。这样的效果 可能有助于目前在全球遇到的肥胖和T2DM的加速发生率。 我们将开发一种鼠标模型，以使用遗传施加的母体胰岛素来研究此问题 抵抗是肥胖的替代物。在初步研究中，我们发现母体胰岛素抵抗会影响 后代的肥胖和胰岛素稳态。该项目的具体目的是：1）使用此鼠标 评估母体胰岛素抵抗和与母体高脂饮食相互作用的模型 后代的组成和能量和胰岛素稳态； 2）检查 这种母体胰岛素抵抗会影响的分子/发育机制 下丘脑进食电路的发展。 我们将对母体胰岛素抵抗对的后果进行全面分析 后代中的能量和胰岛素稳态，并扩展了我们模型的分析以考虑效果 孕产妇饮食的脂肪含量。我们将评估母体胰岛素抵抗对 下丘脑中的发育过程，最初着重于弧形核。效果 母体胰岛素抵抗对弧形核的发育的耐药性将通过定量评估 分析三个功能不同的弧形神经元种群的细胞体（POMC，NPY和RIP 神经元）及其对下丘脑次级靶标的轴突预测。 定义时间窗口和对妊娠和早期外次效应的易感性的机制 关于母体胰岛素抵抗的后代，应为相应的重要见解 人类易感性的窗口。从长远来看，定义影响的相关产妇信号 发育中的大脑中的分子事件可能会导致预防新型策略的设计 人类肥胖/T2DM。