Regulation of hepatic substrate flux by leptin via POMC neurons and hepatocytes

瘦素通过 POMC 神经元和肝细胞调节肝底物流量

• 批准号: 8487917
• 负责人: Eric Berglund
• 金额: $ 10.18万
• 依托单位: UT SOUTHWESTERN 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: 2013-05-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487917
• 关键词: Animals; Award; Blood Glucose; Body Weight; Brain; Cell Respiration; Citric Acid Cycle; Complement; Data; Defect; Development; Disease; Dyslipidemias; Environment; Equipment; Fasting; Fatty Liver; Foundations; Future; Gene Expression; Genes; Genotype; Glucose; Goals; Hand; Health; Hepatic; Hepatocyte; Hormones; Hyperglycemia; Hypothalamic structure; Individual; Insulin Resistance; Isotopes; Knockout Mice; Laboratories; Leptin; Lipids; Liver; Mass Spectrum Analysis; Measurement; Measures; Mediating; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Molecular; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Obesity; Pathogenesis; Pathway interactions; Pharmacotherapy; Physiological; Plasma; Publishing; Reagent; Receptor Signaling; Regulation; Reporting; Research; Scientist; Signal Transduction; Site; Solid; Structure of nucleus infundibularis hypothalami; Symptoms; Techniques; Testing; Tracer; Training; Triglyceride Metabolism; Triglycerides; Work; base; career; combat; energy balance; feeding; functional outcomes; glucose metabolism; glucose production; improved; in vivo; innovation; insulin sensitivity; leptin receptor; lipid biosynthesis; lipid metabolism; liver metabolism; metabolomics; mouse model; novel; oxidation; protein expression; public health relevance; research study; skills; stable isotope; tool; trafficking

DESCRIPTION (provided by applicant): The basis for this K01 application is to study how the hormone leptin acts in both the brain and liver to positively regulate hepatic glucose and lipid flux and thus mitigate hyperglycemia and insulin resistance. To do so, I will develop expertise during the award period using stable isotope tracer techniques combined with mass spectrometry and nuclear magnetic resonance analyses of hepatic glucose and lipid fluxes. These are powerful methods that allow study of animals in vivo and measurements of functional effects on metabolic pathways. This will be done under the co-mentorship of Drs. Joel Elmquist and Shawn Burgess laboratory. Current targets of leptin action under study are POMC neurons in the ARH and direct leptin action on hepatocytes to regulate hepatic glucose and lipid metabolism. More traditional analyses of protein expression and gene expression will also be performed to complement in vivo findings related to function and identify specific molecular pathways that may be more directly targeted by pharmacotherapy. Future work could use metabolomic and microarray (or more advanced) approaches to identify unknown or under-appreciated metabolites and genes that vary between various genotypes. The current focus is to understand functional implications of physiological perturbations on flux. This focus does not undervalue or diminish the importance of findings related to molecular signaling or identification of novel regulatory components or targets. Instead, this emphasis recognizes the priority to develop expertise performing these experiments, analyzing/interpreting the data, and the ability to transfer these skills to other questions and/or other environments. Moreover, findings related to differences in molecular signaling and/or novel signaling may be the foundation for my goal to become an independent academic scientist. A final note related to this application is that ALL proposed genetically modified mice, reagents, and necessary equipment are in-hand and available to me for continued use. We are NOT proposing to develop novel research tools during this award period and can thus focus on training and completing the proposed aims.

描述（由申请人提供）：该K01应用的基础是研究激素瘦素如何在大脑和肝脏中起作用，以阳性调节肝葡萄糖和脂质通量，从而减轻高血糖和胰岛素耐药性。为此，我将使用稳定的同位素示踪技术在奖励期间发展专业知识，并结合肝葡萄糖和脂质通量的质谱和核磁共振分析。这些是强大的方法，可以研究动物体内的动物以及对代谢途径的功能效应的测量。这将在Drs的委托下完成。乔尔·埃尔姆奎斯特（Joel Elmquist）和肖恩·伯吉斯（Shawn Burgess）实验室。正在研究的瘦素作用的当前靶标是ARH中的POMC神经元，并在肝细胞上直接瘦素作用以调节肝葡萄糖和脂质代谢。还将对蛋白质表达和基因表达进行更多传统的分析，以补充与功能相关的体内发现，并确定可能更直接地由药物治疗靶向的特定分子途径。未来的工作可以使用代谢组和微阵列（或更先进的）方法来识别各种基因型之间变化的未知或被低估的代谢产物和基因。当前的重点是了解生理扰动对通量的功能含义。这种焦点不会低估或减少与分子信号传导或新型调节组件或目标鉴定有关的发现的重要性。取而代之的是，这种强调认识到开发执行这些实验，分析/解释数据以及将这些技能转移到其他问题和/或其他环境的能力的优先考虑。此外，与分子信号传导和/或新颖信号差异有关的发现可能是我成为独立学术科学家的目标的基础。与此应用程序相关的最终说明是，所有提出的基因修饰的小鼠，试剂和必要的设备均掌握，我可以继续使用。我们不建议在此奖项期间开发新颖的研究工具，因此可以专注于培训并完成拟议的目标。