MECHANISM OF NEURONAL REGULATION BY LEPTIN AND INSULIN

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。最近发现的荷尔蒙瘦素是大脑感知的脂肪储存的主要信号。瘦素对能量摄入和消耗起负反馈作用，而瘦素缺乏会导致吞噬功能亢进和能量消耗减少。然而，关于瘦素如何作用于大脑以传递外周脂肪水平的信号，人们知之甚少。瘦素的主要靶点之一是前阿片黑素皮质素(POMC)神经元。这些下丘脑神经元分泌α-MSH，这是一种抑制摄食和增加能量消耗的神经肽，瘦素直接增加这些神经元的活动，导致α-MSH分泌增加。在以前的研究中，我们确定了瘦素用来敏锐地调节POMC神经元的机制。瘦素的另一个靶点是那些分泌神经肽Y(NPY)和刺鼠相关肽(AGRP)的下丘脑神经元，这两种神经肽可以增加摄食和减少能量消耗。这些不同的神经元可以通过两种不同颜色的荧光蛋白的靶向(转基因)表达进行视觉识别。我们建议进一步描述瘦素对POMC神经元的作用，并将这些研究扩展到NPY神经元，通过测量它们对瘦素处理的电活动的反应。我们将通过分析瘦素在每类神经元中使用的细胞内信号转导通路，以及每类神经元中调节的离子通道，确定瘦素受体如何在直接激活POMC神经元的同时，直接抑制附近的NPY神经元。更好地了解这些途径对于开发肥胖治疗方法至关重要。我们将评估瘦素如何影响那些改变了对瘦素反应的动物的这些神经元，以确定这些神经元是否在动物对瘦素的生理反应中发挥作用。最后，我们将评估饮食诱导肥胖和恶病质消耗综合征动物中这些神经元对瘦素和胰岛素的反应，以确定POMC或NPY/AGRP神经元对能量稳态信号的敏感性变化是否有助于这些衰弱综合征。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The recently discovered hormone leptin is the primary signal of fat stores that is perceived by the brain. Leptin exerts negative feedback effects on energy intake and expenditure, and leptin insufficiency causes hyperphagia and decreased energy expenditure. Yet, little is known about how leptin acts on the brain to relay the signal of peripheral fat levels. One of the major targets of leptin is the proopiomelanocortin (POMC) neurons. These hypothalamic neurons secrete alpha-MSH, a neuropeptide that inhibits feeding and increases energy expenditure, and leptin directly increases the activity of these neurons, causing increased secretion of alpha-MSH. In previous studies we identified the mechanisms that leptin uses to acutely regulate POMC neurons. Another target of leptin is those hypothalamic neurons that secrete neuropeptide Y (NPY) and agouti related peptide (AGRP), neuropeptides that increase feeding and decrease energy expenditure. These different neurons can be visually identified by the targeted (transgenic) expression of 2 different colored fluorescent proteins. We propose to further characterize the actions of leptin on POMC neurons, and to extend these studies to the NPY neurons, by measuring their electrical activity in response to leptin treatment. We will determine how the leptin receptor can activate directly POMC neurons while directly inhibiting nearby NPY neurons by analyzing the intracellular signal transduction pathways used by leptin in each type of neuron, and the ion channels that are modulated in each class of neuron. A better understanding of these pathways is essential to develop therapies for obesity. We will evaluate how leptin affects these neurons in animals that have altered responses to leptin, to determine if these neurons play a role in the animals' physiological response to leptin. Finally, we will assess the response of these neurons to leptin and insulin in animals with diet-induced obesity and with a cachectic wasting syndrome, to determine if changes in the sensitivity of the POMC or NPY/AGRP neurons to signals of energy homeostasis contribute to these debilitating syndromes.