Orexin Induced Gene and Protein Expression Patterns in the rLH

rLH 中食欲素诱导的基因和蛋白质表达模式

• 批准号: 8774188
• 负责人: Tammy Angaline Butterick
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774188
• 关键词: Animals; Biogenesis; Brain; Caring; Cell model; Cost Savings; DUSP1 gene; Development; Diet; Direct Costs; Disabled Persons; Energy Metabolism; Environment; Exercise; Gene Expression; Gene Proteins; General Population; Genes; Genetic; Goals; Health; Healthcare Systems; Hypothalamic structure; Hypoxia Inducible Factor; In Vitro; Individual; Inherited; Injection of therapeutic agent; Intervention; Investigation; Lateral; Lead; MAPK11 gene; Maintenance; Mediating; Medical; Metabolic; Metabolism; Mitochondria; Mitogen-Activated Protein Kinases; Mitogens; Morbidity - disease rate; Mus; Neuraxis; Neurologic; Neurons; Neuropeptides; Obesity; Outcome; Overweight; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Pattern; Peptides; Phosphotransferases; Physical activity; Prevalence; Production; Rattus; Regulation; Reporting; Research; Resistance; Role; Signal Transduction; Source; Testing; Therapeutic; Thermogenesis; Tissues; Transcription Coactivator; Translating; Veterans; Weight Gain; Weight maintenance regimen; Work; cost; economic impact; energy balance; hypocretin; improved; in vitro testing; in vivo; in vivo Model; inhibitor/antagonist; innovation; inorganic phosphate; interest; mortality; neuronal survival; new therapeutic target; novel; novel strategies; obesity risk; obesity treatment; orexin A; prevent; protein expression; receptor; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Obesity has increased in prevalence worldwide, which is thought to be due to the influences of an obesity-promoting environment and genetic factors. Despite these influences there are individuals and animals that resist obesity. Spontaneous physical activity (SPA), which generates nonexercise activity thermogenesis (NEAT), can reduce weight gain. Injections of hypothalamic neuropeptide orexin A (OxA) into the lateral rostral hypothalamus (rLH) increased levels of SPA and increase obesity resistance. The neurological mechanism that drive SPA are not fully defined. Understanding the mechanism(s) by which NEAT is regulated will have the potential to develop novel approaches to preventing and treating obesity. OxA has been shown to activate extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 mitogen activated phosphate kinase (MAPK) in various cell models. Mice globally lacking the inhibitor for both these kinases, MKP-1, have been reported to be obesity resistant due in part to an increase in energy expenditure and SPA, but it is unknown whether OxA signaling is altered. OxA has also been recently shown to increase ATP and the transcription factor hypoxia inducible factor-1a (HIF-1a) in hypothalamic tissue under normoxic conditions. This is noteworthy given that HIF-1a increases oxidative phosphorylation. Additional independent studies have shown that HIF-1a expression is regulated in part by MAPKs and the transcriptional coactivator PGC-1a. PGC-1a is a regulator of mitochondrial biogenesis, can simultaneously upregulate genes that protect against oxidative stress, and increases ATP production. The central hypothesis proposed in this application is: SPA effects on weight gain depend in part on OxA signaling in the rLH, which alters genes and proteins involved in short- and long-term intracellular metabolic function. The three specific aims that will test this hypothesis are: 1) Determine in vitro if OxA increases HIF-1¿ by the activation of ERK1/2 and p38 MAPKs. 2) Test in vitro whether OxA-induced activation of HIF-1¿ mediates intracellular metabolic changes in rat rLH sections. 3) Evaluate in vivo if OxA treatment ameliorates or prevents changes in the ERK1/2-p38-MAPK-HIF-1¿- PGC-1¿ pathway and intracellular metabolic responsiveness in the rLH following the development of diet-induced obesity. The immediate goal of the work proposed will characterize cellular mechanisms important in OxA-induced SPA using in vitro and in vivo models, with a long-term goal of developing therapeutic treatments for obesity through pharmacological manipulation of these identified pathways. The expected outcome is that OxA will increase the short- and long-term intracellular metabolic capacity of activated neurons, resulting in the maintenance of elevated SPA and obesity resistance. This will impact the field of obesity research by identifying a mechanism through which intracellular OxA signaling might contribute to obesity resistance. The innovation and the challenge to current paradigms are that the proposed studies suggest a new mechanism through which OxA elevates SPA, which is by altering genes that increase intracellular metabolic resistance in activated rLH neurons. This mechanism may be responsible for conferring long-term obesity resistance and would provide a new therapeutic target for obesity.

描述（由申请人提供）： 全球肥胖患病率有所增加，这被认为是由于促进肥胖的环境和遗传因素的影响。尽管存在这些影响，但仍有一些人和动物能够抵抗肥胖。自发体力活动 (SPA) 会产生非运动性活动产热 (NEAT)，可以减少体重增加。将下丘脑神经肽食欲素 A (OxA) 注射到下丘脑外侧头侧 (rLH) 可以增加 SPA 水平并增强肥胖抵抗力。驱动 SPA 的神经机制尚未完全明确。了解 NEAT 的调节机制将有可能开发出预防和治疗肥胖的新方法。 OxA 已被证明可以在各种细胞模型中激活细胞外信号调节激酶 1/2 (ERK1/2) 和 p38 丝裂原激活磷酸激酶 (MAPK)。据报道，全球范围内缺乏这两种激酶抑制剂 MKP-1 的小鼠具有肥胖抵抗力，部分原因是能量消耗和 SPA 增加，但尚不清楚 OxA 信号传导是否发生改变。最近还显示，在常氧条件下，OxA 可以增加下丘脑组织中的 ATP 和转录因子缺氧诱导因子-1a (HIF-1a)。鉴于 HIF-1a 会增加氧化磷酸化，这一点值得注意。其他独立研究表明，HIF-1a 表达部分受 MAPK 和转录共激活因子 PGC-1a 调节。 PGC-1a 是线粒体生物发生的调节剂，可以同时上调防止氧化应激的基因，并增加 ATP 的产生。本申请提出的中心假设是：SPA 对体重增加的影响部分取决于 rLH 中的 OxA 信号传导，该信号改变参与短期和长期细胞内代谢功能的基因和蛋白质。 检验这一假设的三个具体目标是： 1) 体外确定 OxA 是否增加 HIF-1¿ 通过 ERK1/2 和 p38 MAPK 的激活。 2) 体外测试 OxA 诱导的 HIF-1¿ 激活是否介导大鼠 rLH 切片的细胞内代谢变化。 3) 体内评估 OxA 治疗是否改善或预防饮食引起的肥胖发生后 ERK1/2-p38-MAPK-HIF-1¿-PGC-1¿ 通路和 rLH 细胞内代谢反应的变化。这项工作的近期目标是利用体外和体内模型来表征 OxA 诱导的 SPA 中重要的细胞机制，长期目标是通过对这些已确定的途径进行药理学操作来开发肥胖症的治疗方法。预期结果是，OxA 将增加激活神经元的短期和长期细胞内代谢能力，从而维持升高的 SPA 和肥胖抵抗力。这将通过识别影响肥胖研究领域 细胞内 OxA 信号传导可能有助于抵抗肥胖的机制。对当前范式的创新和挑战在于，拟议的研究提出了一种 OxA 升高 SPA 的新机制，即通过改变增加激活的 rLH 神经元细胞内代谢抵抗的基因。这种机制可能有助于赋予长期肥胖抵抗力，并为肥胖提供新的治疗靶点。