Leptin Signaling in Hypothalamic Neurons and Glutamate Receptors

下丘脑神经元和谷氨酸受体中的瘦素信号传导

• 批准号: 8661767
• 负责人: YOUNG-BUM KIM
• 金额: $ 37.28万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-19 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661767
• 关键词: Acute; Affect; Body Weight; Brain; C-terminal; Cell Line; Data; Dendrites; Desire for food; Development; Eating; Energy Intake; Fatty acid glycerol esters; Future; Glutamate Receptor; Glutamates; Hormones; Human; Hypothalamic structure; In Vitro; Injection of therapeutic agent; Laboratories; Lead; Leptin; Leptin deficiency; Mediating; Methodology; Morphology; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neurobiology; Neuronal Plasticity; Neurons; Obesity; Pathway interactions; Phosphorylation; Play; Receptor Signaling; Regulation; Rodent; Role; Signal Pathway; Signal Transduction; Slice; Structure; Synapses; Testing; Tyrosine; Tyrosine Phosphorylation; density; energy balance; feeding; in vivo; leptin receptor; mind control; neuronal excitability; novel; receptor; response; synaptogenesis

DESCRIPTION (provided by applicant): The fat-derived hormone leptin acts on neurons in the hypothalamus to regulate food intake and body weight in rodents and humans. The aim of this proposal is to identify and characterize a novel signaling mechanism whereby leptin affects neuronal activity of POMC and AgRP neurons. Specifically, we will test the hypothesis that leptin receptors localized on dendrites of POMC and AGRP neurons regulates phosphorylation and activity of post-synaptic glutamate receptors (NMDA-R(NR1/NR2B)), and that this pathway influences dendrite morphology, and eventually plays a role in energy balance regulation in mice. To achieve this, we will investigate leptin receptor signaling and action in cell lines, primary neuronal cultures, brain slices and in vivo in mice. We will use state- of-the art methodologies and create/use novel genetically modified mice, and study leptin's effects on neuronal plasticity and on energy balance in mice lacking specific NMDA receptor subunits in POMC or AgRP neurons. Findings from this proposal will lead to a significant advancement in our understanding of leptin receptor neurobiology. We will elucidate a new CNS pathway whereby leptin regulates energy balance.

描述（由申请人提供）：脂肪衍生的激素瘦素作用于下丘脑中的神经元，以调节啮齿动物和人类的食物摄入量和体重。该建议的目的是识别和表征一种新型的信号传导机制，从而瘦素会影响POMC和AGRP神经元的神经元活性。具体而言，我们将检验以下假设：瘦素受体局部在POMC和AGRP神经元的树突上调节磷酸化和突触后谷氨酸受体的磷酸化和活性（NMDA-R（NR1/NR2B）），并且这种途径可以影响树突状的形式，并最终会在能量范围内呈现出来。为此，我们将研究瘦素受体信号传导和在细胞系，原发性神经元培养物，脑切片和小鼠体内的作用。我们将使用状态的艺术方法，并创建/使用新型的遗传改性小鼠，并研究瘦素对神经元可塑性的影响以及缺乏POMC或AGRP神经元缺乏特定NMDA受体亚基的小鼠的能量平衡。该提案的发现将导致我们对瘦素受体神经生物学的理解的重大进步。我们将阐明一种新的CNS途径，从而调节能量平衡。