Leptin Signaling in Hypothalamic Neurons and Glutamate Receptors

描述（由申请人提供）：脂肪衍生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和体重。本提案的目的是确定和表征一种新的信号传导机制，瘦素影响POMC和AgRP神经元的神经元活性。具体来说，我们将测试的假设，瘦素受体位于树突的POMC和AGRP神经元调节磷酸化和突触后谷氨酸受体（NMDA-R（NR 1/NR 2B））的活性，这条途径影响树突形态，并最终在小鼠的能量平衡调节中发挥作用。为了实现这一目标，我们将研究瘦素受体信号转导和行动在细胞系，原代神经元培养，脑切片和在小鼠体内。我们将使用最先进的方法并创建/使用新的遗传修饰小鼠，并研究瘦素对POMC或AgRP神经元中缺乏特异性NMDA受体亚基的小鼠的神经元可塑性和能量平衡的影响。这一建议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。我们将阐明一个新的中枢神经系统途径，瘦素调节能量平衡。

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.