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

描述(申请人提供)：厌食症-恶病质的发生是因为大脑对能量缺乏的检测因细胞因子过多而受损。弓状神经肽Y(NPY)神经元通常在能量缺乏时激活合成代谢过程，以恢复能量平衡。大约40%的NPY神经元也是葡萄糖抑制神经元(NPY-GI)。我们实验室最近的工作表明，禁食增加了NPY神经元中CFos的激活。禁食还会增加NPY的释放，以应对血糖下降，部分是通过使NPY-GI神经元对血糖下降敏感。这是由AMP激活的蛋白激酶(AMPK)介导的。这项建议旨在研究NPY-GI神经元在疾病相关厌食-恶病质发展中的作用。神经肽Y神经回路在厌食症-恶病质期间功能障碍。内毒素，脂多糖(LPS)，会导致厌食症，并阻止禁食诱导的弓状CFOS激活的增加。内毒素对厌食症的中枢作用部分是由炎性细胞因子肿瘤坏死因子α(TNFpha)介导的。肿瘤坏死因子α抑制骨骼肌中的AMPK。我们假设，在厌食症-恶病质期间，肿瘤坏死因子α水平的增加削弱了NPY-GI神经元对AMPK抑制导致的血糖下降的反应能力。这一假设将通过两个具体目标进行检验。具体目标1将确定厌食剂量的内毒素是否阻止禁食诱导的NPY-GI神经元的变化。具体目标2将确定TNFpha是否通过抑制AMPK来钝化NPY-GI神经元对血糖降低的反应。特殊目标2还将评估可能使NPY-GI神经元的葡萄糖敏感性正常化的信号通路。人们对厌食症-恶病质中枢功能障碍的细胞机制知之甚少，但这种综合征导致了20%的慢性病患者死亡，如癌症、艾滋病和心力衰竭。本文提出的研究将提供一个清晰的框架，以了解NPY-GI神经元在厌食-恶病质期间是如何受损的。这些研究将导致疾病相关厌食症-恶病质的治疗方法的开发，这将显着提高一些慢性病的存活率。公共卫生相关性：我们假设正常的禁食诱导的NPY神经元的变化在厌食症-恶病质期间被阻断，导致合成代谢过程的激活受损和危及生命的消瘦。这在一定程度上是因为炎性细胞因子肿瘤坏死因子(TNF)削弱了NPY神经元通过抑制AMP激活的蛋白激酶(AMPK)而感觉到血糖下降的能力。

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).