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: 8442780
• 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/8442780
• 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; public health relevance; 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）： 肥胖症在全球范围内有所增加，这被认为是由于对象促进环境和遗传因素的影响。尽管有这些影响，但仍然有抵抗肥胖症的个人和动物。自发的体育活动（SPA）会产生非耐受活动热发生（整洁），可以减轻体重增加。向下丘脑神经肽OREXIN A（OXA）注射到外侧下丘脑（RLH）中增加了水疗水平并增加了肥胖耐药性。驱动水疗中心的神经系统机制尚未完全定义。了解整洁的调节机制将有可能开发预防和治疗肥胖症的新方法。已显示OXA在各种细胞模型中都活化可激活细胞外信号调节激酶1/2（ERK1/2）和P38有丝分裂原激活的磷酸激活激酶（MAPK）。据报道，全球缺乏这些激酶MKP-1抑制剂的小鼠据报道是肥胖的，部分原因是能量消耗和水疗中心增加，但未知OXA信号是否改变了。最近还显示，在常氧化条件下，OXA在下丘脑组织中增加了ATP和转录因子缺氧诱导因子1a（HIF-1A）。值得注意的是，HIF-1A会增加氧化磷酸化。其他独立研究表明，HIF-1A表达部分由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，可以简单地上调预防氧化应激的基因，并增加ATP的产生。本应用中提出的中心假设是：水疗对体重增加的影响部分取决于RLH中的OXA信号传导，从而改变了参与短期和长期细胞内代谢功能的基因和蛋白质。 测试该假设的三个特定目的是：1）确定在体外确定OXA是否增加 HIF-1通过ERK1/2和P38 MAPK的激活。 2）在体外测试OXA诱导的HIF-1的激活是否介导大鼠RLH切片的细胞内代谢变化。 3）在体内评估OXA治疗是否可以缓解或防止ERK1/2-P38-MAPK-HIF-1¿-PGC-1？-PGC-1？ - 饮食诱导的肥胖症发展后RLH中的PGC-1。途径和细胞内代谢反应性。提出的工作的直接目标将使用体外和体内模型来表征在OXA诱导的SPA中重要的细胞机制，其长期目标是通过对这些鉴定出的途径的药物操纵来开发治疗治疗方法。预期的结果是，OXA将增加活化神经元的短期和长期细胞内代谢能力，从而维持升高的水疗中心和肥胖性耐药性。这将通过识别来影响肥胖研究领域 细胞内OXA信号传导可能导致肥胖性抗性的机制。当前范式的创新和挑战是拟议的研究提出了一种新的机制，该机制通过该机制提高了SPA，该机制是通过改变增加活化RLH神经元中细胞内代谢性的基因。这种机制可能是赋予长期肥胖耐药性的原因，并将为肥胖提供新的治疗靶点。