Hormonal and Nutritional Regulation of Hypothalamic Neurogenesis

下丘脑神经发生的激素和营养调节

• 批准号: 7988149
• 负责人: Sebastien G Bouret
• 金额: $ 35.64万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988149
• 关键词: Address; Adipocytes; Adolescent; Adult; Affect; Appetite Regulation; Attention; Birth; Body Weight; Brain; Bromodeoxyuridine; Caloric Restriction; Cell Count; Cell Nucleus; Cell Proliferation; Cells; Deoxyuridine; Development; Diabetes Mellitus; Diet; Disease; Elderly; Embryo; Embryonic Development; Environment; Event; Exposure to; Fatty acid glycerol esters; Goals; Hormonal; Hormones; Human; Hypothalamic structure; In Vitro; Incidence; Individual; Leptin; Leptin deficiency; Life; Longevity; Malnutrition; Measures; Mediating; Metabolic; Metabolism; Methods; Mus; Neonatal; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Overnutrition; Pathway interactions; Pattern; Perinatal; Physiological; Play; Population; Predisposition; Pregnancy; Pro-Opiomelanocortin; Regulation; Relative (related person); Reporting; Research; Risk; Rodent; Role; Signal Transduction; Structure; Supplementation; TdT-Mediated dUTP Nick End Labeling Assay; Techniques; Testing; Time; Work; critical period; energy balance; feeding; fetal; in vitro Assay; in vitro testing; insight; leptin receptor; mRNA Expression; mother nutrition; neurogenesis; neuronal survival; neuropeptide Y; novel therapeutics; offspring; postnatal; prenatal; programs; public health relevance

DESCRIPTION (provided by applicant): The incidence of juvenile obesity and type 2 diabetes is at an all time high, yet neonatal factors that contribute to these diseases are poorly understood. The long-range goal of this project is to clarify how the adipocyte-derived hormone leptin influences, during the embryonic life, the development of neuroendocrine pathways that control body weight and energy balance in mice. Central to this goal is determining how leptin affects neurogenesis in hypothalamic nuclei known to regulate metabolism throughout the lifespan. The overall hypothesis addressed in this proposal is that leptin acts directly on the hypothalamus during the embryonic life to influence neurogenesis of hypothalamic neurons playing a role in the regulation of body weight and energy balance. We also suggest that alteration of maternal nutrition affects neurogenesis in the hypothalamus of the offspring. Both physiological and in vitro experimental approaches will be used to test these hypotheses by addressing the following specific aims. Specific Aim 1. We propose to use histochemical techniques and in vitro assays to test the neurogenic activity of leptin in embryos that lack leptin (Lepob/Lepob mice). Specific Aim 2. We will evaluate the ability of embryonic leptin exposure to functionally rescue neurodevelopmental and metabolic deficits in Lepob/Lepob mice. Specific Aim 3. Finally, we will explore the developmental consequences of maternal over- and undernutrition on hypothalamic neurogenesis in the offspring and determine whether maternal leptin treatment can influence hypothalamic neurogenesis in the offspring of undernourished (hypoleptinemic) dams. The results of the proposed research will expand our appreciation of leptin to include a profound developmental activity that promotes proliferation of hypothalamic neurons that regulate body weight and energy balance. These studies may also provide new insight into the mechanisms by which alteration of prenatal nutritional environment leads to obesity and diabetes in the offspring, and may provide new therapeutic opportunities. PUBLIC HEALTH RELEVANCE: The long-range goal of this project is to clarify how perinatal hormones, particularly the fat- derived hormone leptin, influence development brain structures involved in appetite regulation and how changes in the maternal environment during critical periods of life may have long-term consequences for regulation of body weight in the offspring. These studies may open new avenues for understanding pre- and perinatally acquired predisposition to later disease (particularly obesity), and may provide new therapeutic opportunities.

描述(申请人提供)：青少年肥胖症和2型糖尿病的发病率一直很高，但导致这些疾病的新生儿因素却知之甚少。该项目的长期目标是阐明脂肪细胞衍生的激素瘦素在胚胎生活中如何影响控制小鼠体重和能量平衡的神经内分泌途径的发展。这一目标的核心是确定瘦素如何影响下丘脑核团中的神经发生，已知的是在整个生命周期中调节新陈代谢。这一建议提出的总体假设是，瘦素在胚胎期间直接作用于下丘脑，影响下丘脑神经元的神经发生，在调节体重和能量平衡方面发挥作用。我们还认为，母体营养的改变会影响子代下丘脑的神经发生。生理学和体外实验方法都将被用来测试这些假说，以解决以下具体目标。具体目的1.我们建议使用组织化学技术和体外实验来检测缺乏瘦素的胚胎(Lepob/Lepob小鼠)中瘦素的神经发生活性。具体目的2.我们将评估胚胎瘦素暴露对LEPOB/LEPOB小鼠神经发育和代谢缺陷的功能性修复能力。具体目的3.最后，我们将探讨母体营养过度和营养不足对子代下丘脑神经发生的发育影响，并确定母体瘦素治疗是否会影响营养不良(低蛋白血症)母鼠的子代下丘脑神经发生。拟议的研究结果将扩大我们对瘦素的理解，包括一种深刻的发育活动，促进调节体重和能量平衡的下丘脑神经元的增殖。这些研究还可能对产前营养环境改变导致后代肥胖和糖尿病的机制提供新的见解，并可能提供新的治疗机会。公共卫生相关性：该项目的长期目标是阐明围产期激素，特别是脂肪衍生激素瘦素如何影响参与食欲调节的大脑结构的发育，以及生命关键时期母亲环境的变化如何对后代的体重调节产生长期影响。这些研究可能为了解先天和围产期后天疾病(特别是肥胖)的易感性开辟新的途径，并可能提供新的治疗机会。