Mechanism of Neuronal Regulation by Leptin and Insulin

描述（由申请人提供）：瘦素是大脑感知的能量储存的主要信号。 然而，人们对瘦素如何作用于大脑以传递外周脂肪水平的信号知之甚少。 我们已经确定了瘦素向脑细胞发出信号的部分机制。 瘦素的至少一个主要靶点是下丘脑中的一组细胞，这些细胞分泌α-MSH，一种已知抑制进食和增加能量消耗的神经肽。 我们认为瘦素的另一个靶点是分泌NYP的下丘脑神经元，NYP是一种增加进食和减少能量消耗的神经肽。 此外，我们提出瘦素将以相反的方式作用于NPY神经元，它将抑制它们。 我们将通过测量POMC和NPY/AGRP神经元对瘦素处理的电活动来确定瘦素对它们的作用。 通过靶向（转基因）表达2种不同颜色的荧光蛋白，目视鉴别不同的神经元。 我们将通过分析瘦素在每种类型的神经元中使用的信号转导途径，以及在每类神经元中调节的离子通道，来确定瘦素受体如何在两个神经元群体中具有如此不同的肌动蛋白。 我们将试图表明，这些神经元是瘦素“通知”大脑脂肪储存的主要方式，我们将确定瘦素信号是否会在瘦素对其正常作用有不同影响的情况下发生变化。

DESCRIPTION (provided by applicant): Leptin is the primary signal of energy stores that is perceived by the brain. Yet little is known about how leptin acts on the brain to carry that signal of peripheral fat levels. We have identified part of the mechanism that leptin uses to signal to brain cells. At least one of the major targets of leptin is a group of cells in the hypothalamus, these cells secrete a-MSH, a neuropeptide known to inhibit feeding and to increase energy expenditure. We propose that another target of leptin will be those hypothalamic neurons that secrete NYP, a neuropeptide that increases feeding and decreases energy expenditure. Furthermore, we propose that leptin will act in the opposite way on NPY neurons, it will inhibit them. We will determine the actions of leptin on POMC and NPY/AGRP neurons by measuring their electrical activity in response to leptin treatment. The different neurons will be visually identified by the targeted (transgenic) expression of 2 different colored fluorescent proteins. We will determine how the leptin receptor can have such different actin is the two neuronal populations by analyzing the signal transduction pathways used by leptin in each type of neuron, and the ion channels that are modulated in each class of neuron. We will attempt to show that these neurons are a major way that leptin "informs" the brain about adipose stores, and we will determine if this leptin signal is changed in situations when leptin has different effect to its normal role.