Leptin and development of glucagon-like peptide-1(GLP-1)neural circuits controlling ingestive behavior

瘦素与胰高血糖素样肽-1（GLP-1）神经回路控制摄取行为的发育

• 批准号: 9386309
• 负责人: Jessica Erin Biddinger
• 金额: $ 0.08万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386309
• 关键词: Adipocytes; Adolescent; Adult; Affect; Architecture; Axon; Behavior; Biological Neural Networks; Body Weight; Brain; Cells; Child; Complex; Development; Dorsal; Eating; Energy Metabolism; Exhibits; Feeding behaviors; Goals; Health; Health Care Costs; Heart Diseases; Homeostasis; Hormonal; Hormones; Hyperphagia; Hypothalamic structure; Immunohistochemistry; Impairment; International; Label; Lead; Leptin; Life; Link; Location; Maintenance; Metabolic; Metabolism; Methods; Molecular; Molecular Genetics; Mus; Neural Pathways; Neuraxis; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Nutritional; Nutritional status; Obese Mice; Obesity; Outcome; Overweight; Pathway interactions; Pattern; Physiological; Physiological Processes; Physiology; Play; Population; Prevalence; Process; Regulation; Research Proposals; Risk; Role; Satiation; Signal Transduction; Site; Specific qualifier value; Structure of nucleus infundibularis hypothalami; Testing; Time; Training; United States; Viscera; Visceral; biological adaptation to stress; cellular imaging; cost; critical period; energy balance; experimental study; gain of function; gastrointestinal; genetic approach; glucagon-like peptide 1; hindbrain; imaging modality; incretin hormone; leptin receptor; loss of function; metabolic rate; mouse model; nerve supply; neural circuit; neurodevelopment; neurotransmission; neurotrophic factor; obesity in children; paraventricular nucleus; postnatal; programs; public health relevance; receptor; receptor expression; relating to nervous system; response

 DESCRIPTION (provided by applicant): Childhood obesity has increased in the United States and internationally, which sets up young people for a lifetime of devastating and costly health problems. The neural networks that regulate metabolic homeostasis must develop appropriately in order to function properly in adulthood. Neural circuits that develop under abnormal environmental conditions can become disrupted and no longer function normally, which can lead to obesity and associated negative health consequences. The nucleus of the solitary tract (NTS) in the hindbrain receives and integrates visceral nutritional status, and primarily sends this information to the paraventricular nucleus of the hypothalmus (PVH), which coordinates energy balance and neuroendocrine responses. Leptin receptors (LepRb) in NTS neurons have been shown to impact food intake and metabolic rate. In addition to leptin's role in satiety signaling, it also functions as a neurotrophic factor in development. Leptin is required for normal axon outgrowth from the arcuate nucleus of the hypothalamus to the PVH. Because leptin receptors are expressed by neurons in the NTS during development (including a large proportion of GLP-1 neurons), leptin may direct formation of this pathway. Experiments proposed in Specific Aim 1 will test whether leptin is required for normal development of neural projections from GLP-1 neurons in the NTS to the PVH. Genetically targeted axonal labels and immunohistochemistry will be used to visualize and quantify GLP-1 neurons in the NTS and their projections in leptin-deficient Lepob/ob mice in development and adulthood. Experiments proposed in Specific Aim 2 will utilize a molecular genetic approach to establish the site of action for leptin's neurotrophic action on NTS GLP-1 neurons and characterize the physiological role of this pathway. Together these studies promise to establish the GLP-1 projection pathway from the NTS to the PVH as a developmentally programmable substrate that determines significant aspects of metabolic physiology.

 描述（由申请人提供）：儿童肥胖症在美国和国际上有所增加，这使年轻人一生都面临毁灭性且代价高昂的健康问题。调节代谢稳态的神经网络必须适当发育才能在成年后正常发挥作用。在异常环境条件下发育的神经回路可能会受到干扰，不再正常运作，这可能导致肥胖和相关的负面健康后果。后脑孤束核（NTS）接收并整合内脏营养状态，并主要将此信息发送至下丘脑室旁核（PVH），后者协调能量平衡和神经内分泌反应。 NTS 神经元中的瘦素受体 (LepRb) 已被证明会影响食物摄入和代谢率。瘦素除了在饱腹感信号传导中发挥作用外，还在发育过程中充当神经营养因子。正常需要瘦素 轴突从下丘脑的弓状核生长到PVH。由于瘦素受体在发育过程中由 NTS 中的神经元（包括大部分 GLP-1 神经元）表达，因此瘦素可能指导该通路的形成。具体目标 1 中提出的实验将测试从 NTS 中的 GLP-1 神经元到 PVH 的神经投射的正常发育是否需要瘦素。基因靶向轴突标记和免疫组织化学将用于可视化和量化 NTS 中的 GLP-1 神经元及其在发育和成年期瘦素缺陷 Lepob/ob 小鼠中的投影。具体目标 2 中提出的实验将利用分子遗传学方法来确定瘦素对 NTS GLP-1 神经元的神经营养作用的作用位点，并表征该途径的生理作用。这些研究共同有望建立从 NTS 到 PVH 的 GLP-1 投射途径，作为决定代谢生理学重要方面的发育可编程底物。