Role of neuropeptide Y-glucose inhibited (NPY-GI) neurons in cytokine-induced ano

描述（由申请人提供）：厌食症-恶病质的发生是由于细胞因子过量导致大脑对能量不足的检测受损。弓形神经肽Y （NPY）神经元通常在能量不足时激活合成代谢过程，以恢复能量稳态。大约40%的NPY神经元也是葡萄糖抑制神经元（NPY- gi）。我们实验室最近的研究表明，禁食会增加NPY神经元的cfo激活。禁食也增加了NPY释放，以响应葡萄糖的降低，部分原因是NPY- gi神经元对葡萄糖的降低敏感。这是由amp活化蛋白激酶（AMPK）介导的。本研究旨在研究NPY-GI神经元在疾病相关性厌食症-恶病质发生中的作用。厌食症-恶病质时NPY神经回路功能失调。内毒素，脂多糖（LPS），引起厌食症和防止空腹引起的弓形cfo激活的增加。脂多糖对厌食症的中心作用部分是由炎症细胞因子肿瘤坏死因子（TNFalpha）介导的。TNFalpha抑制骨骼肌AMPK。我们假设，在厌食症-恶病质期间，TNFalpha水平的升高削弱了NPY-GI神经元对AMPK抑制导致的葡萄糖下降的反应能力。这一假设将通过两个具体目标来验证。特异性目的1将确定厌食剂量的LPS是否阻断禁食诱导的NPY-GI神经元的变化。特异性Aim 2将确定TNFalpha是否通过抑制AMPK来减弱NPY-GI神经元对葡萄糖降低的反应。Specific Aim 2还将评估可能使NPY-GI神经元葡萄糖敏感性正常化的信号通路。关于厌食症-恶病质中枢性功能障碍的细胞机制知之甚少，然而这种综合征是造成慢性疾病（如癌症、艾滋病和心力衰竭）患者死亡的20%的原因。本文提出的研究将为了解NPY-GI神经元在厌食症-恶病质期间如何受损提供一个清晰的框架。这些研究将导致疾病相关厌食症-恶病质治疗的发展，这将显著提高许多慢性疾病期间的生存率。公共卫生相关性：我们假设，在厌食症-恶病质期间，正常的禁食诱导的NPY神经元变化被阻断，导致合成代谢过程的激活受损和危及生命的消耗。发生这种情况的部分原因是炎症细胞因子肿瘤坏死因子α (TNF)通过抑制amp活化蛋白激酶（AMPK）减弱了NPY神经元感知葡萄糖减少的能力。

DESCRIPTION (provided by applicant): Anorexia-cachexia occurs because detection of energy deficit by the brain becomes impaired due to cytokine excess. The arcuate neuropeptide Y (NPY) neurons normally activate anabolic processes during energy deficit in order to restore energy homeostasis. Approximately 40% of NPY neurons are also glucose-inhibited neurons (NPY-GI). Recent work from our laboratory shows that fasting increases cfos activation in NPY neurons. Fasting also increases NPY release in response to decreased glucose, in part by sensitizing NPY-GI neurons to decreased glucose. This is mediated by AMP-activated protein kinase (AMPK). This proposal is designed to study the role of NPY-GI neurons in the development of disease related anorexia-cachexia. NPY neurocircuitry is dysfunctional during anorexia-cachexia. The endotoxin, lipopolysaccharide (LPS), causes anorexia and prevents fasting-induced increases in arcuate cfos activation. The central effects of LPS on anorexia are mediated, in part, by the inflammatory cytokine, tumor necrosis factor alpha (TNFalpha). TNFalpha inhibits AMPK in skeletal muscle. We hypothesize that increased levels of TNFalpha during anorexia-cachexia blunt the ability of NPY-GI neurons to respond to decreased glucose due to AMPK suppression. This hypothesis will be tested by 2 specific aims. Specific Aim 1 will determine whether an anorectic dose of LPS blocks fasting-induced changes in NPY-GI neurons. Specific Aim 2 will determine whether TNFalpha blunts the response of NPY-GI neurons to decreased glucose via AMPK suppression. Specific Aim 2 will also evaluate signaling pathways which may normalize glucose sensitivity in NPY-GI neurons. Very little is known regarding the cellular mechanisms underlying central dysfunction in anorexia-cachexia, yet this syndrome is responsible for >20% of patients deaths in chronic diseases such as cancer, AIDS and cardiac failure. The studies proposed herein will provide a clear framework on which to understand how NPY-GI neurons become impaired during anorexia-cachexia. These studies will lead to the development of therapies for disease related anorexia-cachexia which will significantly improve survival during a number of chronic diseases. PUBLIC HEALTH RELEVANCE: We hypothesize that normal fasting-induced changes in NPY neurons are blocked during anorexia-cachexia leading to impaired activation of anabolic processes and life- threatening wasting. This occurs, in part, because the inflammatory cytokine, tumor necrosis factor alpha (TNF), blunts the ability of NPY neurons to sense glucose decreases via suppression of AMP-activated protein kinase (AMPK).