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

神经肽 Y-葡萄糖抑制 (NPY-GI) 神经元在细胞因子诱导的 ano 中的作用

• 批准号: 7640143
• 负责人: VANESSA H ROUTH
• 金额: $ 20.59万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640143
• 关键词: 5' -AMP-activated protein kinase; Acquired Immunodeficiency Syndrome; Anorexia; Appetite Depressants; Bacterial Infections; Brain; Cachexia; Categories; Cessation of life; Chronic Disease; Data; Detection; Development; Disease; Disease model; Dose; Dyes; Eating; Endotoxins; Energy Metabolism; Fasting; Functional disorder; Glucose; Heart; Heart failure; Homeostasis; Hypothalamic structure; Image; Inflammatory; Injection of therapeutic agent; Interleukin-1 beta; Kidney Failure; Laboratories; Lead; Life; Lipopolysaccharides; Malignant Neoplasms; Measures; Mediating; Membrane Potentials; Metabolic; Neurons; Patients; Pentoxifylline; Peptides; Peripheral; Play; Process; Production; Protein Kinase; Publishing; Regulation; Role; Saline; Signal Pathway; Skeletal Muscle; Structure of nucleus infundibularis hypothalami; Syndrome; System; Techniques; Testing; Tumor Necrosis Factor-alpha; Wild Type Mouse; Work; cytokine; desensitization; design; extracellular; feeding; improved; neuropeptide Y; neurotransmission; prevent; public health relevance; response; therapy development; tumor necrosis factor-alpha inhibitor; wasting

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).

描述（由申请人提供）：由于细胞因子过量导致大脑能量不足检测受损，从而发生厌食-恶病质。弓状神经肽Y（NPY）神经元通常在能量缺乏期间激活合成代谢过程，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）。我们实验室最近的工作表明，禁食增加了NPY神经元中的cfos激活。禁食还增加响应于降低的葡萄糖的NPY释放，部分地通过使NPY-GI神经元对降低的葡萄糖敏感。这是由AMP激活的蛋白激酶（AMPK）介导的。本研究旨在研究NPY-GI神经元在疾病相关性厌食-恶病质发展中的作用。神经肽Y神经回路在缺氧-恶病质期间功能障碍。内毒素，脂多糖（LPS），导致厌食症，并阻止禁食诱导的弓状cfos激活的增加。LPS对厌食症的中枢作用部分由炎性细胞因子肿瘤坏死因子α（TNF α）介导。TNF α抑制骨骼肌中的AMPK。我们推测，在缺氧-恶病质过程中TNF α水平的升高会减弱NPY-GI神经元对AMPK抑制引起的葡萄糖降低的反应能力。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LPS是否阻断禁食诱导的NPY-GI神经元的变化。具体目标2将确定TNF α是否通过AMPK抑制减弱NPY-GI神经元对葡萄糖降低的反应。具体目标2还将评价可能使NPY-GI神经元中的葡萄糖敏感性正常化的信号传导途径。关于阿尔茨海默病-恶病质中中枢功能障碍的细胞机制知之甚少，但这种综合征是导致>20%的慢性疾病如癌症、AIDS和心力衰竭患者死亡的原因。本文提出的研究将提供一个清晰的框架，了解NPY-GI神经元如何在缺氧-恶病质期间受损。这些研究将导致疾病相关的厌食-恶病质的治疗方法的发展，这将显着提高许多慢性疾病的生存率。公共卫生关系：我们推测，正常的禁食诱导的NPY神经元的变化在缺氧-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。这种情况的发生部分是因为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神经元感知葡萄糖降低的能力。