Impact of maternal hyperleptinemia on health: CNS mechanisms

孕产妇高瘦素血症对健康的影响：中枢神经系统机制

• 批准号: 8423000
• 负责人: Rebecca L Leshan
• 金额: $ 5.39万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423000
• 关键词: Accounting; Acute; Adipocytes; Adult; Adult Children; Affect; Animals; Brain; Cardiovascular Diseases; Cells; Child; DNA; DNA Modification Process; Data; Desire for food; Developed Countries; Development; Diabetes Mellitus; Diet; Energy Metabolism; Epidemic; Female of child bearing age; Functional disorder; Future; Gene Expression; Genes; Genetic; Gestational Diabetes; Goals; Growth; Health; Histones; Homeostasis; Hormones; Hypothalamic structure; Imagery; Incidence; Lactation; Leptin; Life; Link; Low Birth Weight Infant; Maternal Physiology; Mediating; Metabolic; Metabolic syndrome; Modification; Mothers; Mus; Mutation; Neural Pathways; Neurites; Neurons; Neurosecretory Systems; Nutritional; Obesity; Organ; Organism; Pathway interactions; Perinatal; Physiological; Population; Pre-Eclampsia; Predisposition; Pregnancy; Prevention; Process; Regulation; Relative (related person); Reporter Genes; Research; Resistance; Risk; Role; Shapes; Signal Transduction; Structure of nucleus infundibularis hypothalami; Testing; Time; Transgenic Mice; Weight; critical period; developmental genetics; energy balance; feeding; histone modification; in utero; leptin receptor; neural circuit; neurodevelopment; nutrition; obesity treatment; offspring; overexpression; paraventricular nucleus; postnatal; prenatal; programs; public health relevance; resilience

DESCRIPTION (provided by applicant): Obesity and its complications are reaching epidemic proportions in this and other industrialized nations. Women of childbearing age represent a highly affected population, increasing the incidence of acute complications during pregnancy (i.e. preeclampsia and gestational diabetes), as well as long term health consequences in offspring (adult-onset obesity). Given that the perinatal period represents a time of rapid brain development, and that this maturation is sensitive to maternal physiology, these enduring consequences may be caused by stable developmental alterations in brain organization and function. Importantly, studies suggest that leptin (a hormone produced by fat cells that communicates body energy status to the brain) acts as an important factor mediating the correct development of these important weight-regulating circuits. Indeed, leptin administration during this critical perinatal period alters the predisposition to obesity, cardiovascular disease and diabetes later in life in animals exposed to nutritional alterations. In order to understand the role of leptin and leptin signals in the development of hypothalamic neural circuits, we will examine two hypotheses in this application: First, that maternal hyperleptinemia in the absence of obesity will alter the development of projections from hypothalamic arcuate nucleus (ARC) neurons, and that the critical period during which this occurs will be lactation; second, that stable changes to histones and DNA will be induced in offspring of obese mothers that are more susceptible, or more resistant to adult-onset obesity, causing persistent changes in gene expression. We will undertake these studies using mice which over-express leptin to expose offspring to high leptin levels during pregnancy and/or lactation. We will additionally expressing reporter genes in specific populations of cells within the mouse brain, enabling the visualization of neuronal projections from these cells, in addition to examination of expression of genes regulating energy balance. We propose the following specific aims: Specific Aim 1: Determine the contribution of maternal leptin concentration during the pre- and postnatal periods on offspring hypothalamic organization and gene expression. Specific Aim 2: Characterize distinctive and stable covalent modifications of histones and associated genes in the offspring of diet-induced obese (DIO) mothers that demonstrate resistance, or susceptibility to obesity development. These studies will identify mechanisms regulating the development of neural feeding pathways and link these processes to key developmental periods during which an organism's metabolic fate is shaped. These studies will lay the groundwork for future studies of developmental programming in the predisposition to the metabolic syndrome.

描述（由申请人提供）：肥胖及其并发症在这个国家和其他工业化国家已达到流行病的程度。育龄妇女是受影响严重的人群，增加了妊娠期间急性并发症（即先兆子痫和妊娠糖尿病）的发生率，以及对后代的长期健康影响（成人肥胖）。鉴于围产期代表大脑快速发育的时期，并且这种成熟对母体生理机能敏感，这些持久的后果可能是由大脑组织和功能的稳定发育改变引起的。重要的是，研究表明瘦素（一种由脂肪细胞产生的激素，可将身体能量状态传达给大脑）是介导这些重要体重调节回路正确发育的重要因素。事实上，在这一关键的围产期期间给予瘦素会改变营养改变的动物在以后的生活中患肥胖、心血管疾病和糖尿病的倾向。 为了了解瘦素和瘦素信号在下丘脑神经回路发育中的作用，我们将在本申请中检查两个假设：首先，在没有肥胖的情况下，母亲高瘦素血症会改变下丘脑弓状核（ARC）投射的发育）神经元，并且发生这种情况的关键时期是哺乳期；其次，肥胖母亲的后代会诱导组蛋白和 DNA 的稳定变化，这些变化更容易或更能抵抗成人肥胖，从而导致基因表达的持续变化。 我们将使用过度表达瘦素的小鼠进行这些研究，以使后代在怀孕和/或哺乳期间暴露于高瘦素水平。除了检查调节能量平衡的基因的表达之外，我们还将在小鼠大脑内的特定细胞群中表达报告基因，从而使这些细胞的神经元投射可视化。 我们提出以下具体目标： 具体目标 1：确定产前和产后母体瘦素浓度对后代下丘脑组织和基因表达的贡献。具体目标 2：表征饮食诱导肥胖 (DIO) 母亲的后代中组蛋白和相关基因的独特且稳定的共价修饰，这些修饰表现出对肥胖发展的抵抗力或易感性。 这些研究将确定调节神经进食途径发育的机制，并将这些过程与决定生物体代谢命运的关键发育时期联系起来。这些研究将为未来代谢综合征易感性的发育规划研究奠定基础。