Leptin Signaling in Hypothalamic Neurons and Glutamate Receptors

描述（由申请人提供）：脂肪来源的激素瘦素作用于下丘脑的神经元，调节啮齿动物和人类的食物摄入和体重。本提案的目的是确定和表征瘦素影响POMC和AgRP神经元活动的一种新的信号机制。具体而言，我们将验证位于POMC和AGRP神经元树突上的瘦素受体调节突触后谷氨酸受体（NMDA-R(NR1/NR2B)）的磷酸化和活性，并影响树突形态，最终在小鼠能量平衡调节中发挥作用的假设。为了实现这一目标，我们将研究瘦素受体在细胞系、原代神经元培养、脑切片和小鼠体内的信号传导和作用。我们将使用最先进的方法和创建/使用新的转基因小鼠，并研究瘦素对POMC或AgRP神经元中缺乏特定NMDA受体亚基的小鼠神经元可塑性和能量平衡的影响。这项提案的发现将导致我们对瘦素受体神经生物学的理解取得重大进展。我们将阐明瘦素调节能量平衡的新中枢神经系统途径。

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.