Novel Mechanisms Regulating the Adipocyte-Brain Hepatocyte Axis

调节脂肪细胞-脑肝细胞轴的新机制

• 批准号: 8512720
• 负责人: PHILIPP E SCHERER
• 金额: $ 143.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-22 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512720
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Afferent Neurons; Alleles; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Back; Body Weight; Brain; Brain region; CD36 gene; Comorbidity; Complement; Cues; Data; Dietary Fats; Eating; Endocrine; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Event; Fatty acid glycerol esters; Gene Expression; Gene Expression Profile; Genes; Gonadal Steroid Hormones; Hand; Hepatic; Hepatic Mass; Hepatocyte; Homeostasis; Hormones; Hypothalamic structure; Inflammation; Inflammatory; Insulin Receptor; LXRalpha protein; Lead; Light; Link; Lipids; Liver; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methodology; Modeling; Motor; Neural Pathways; Neurons; Neurosecretory Systems; Nodose Ganglion; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Output; PPAR gamma; Pathway interactions; Peripheral; Phenotype; Positioning Attribute; Process; Property; Proteins; Receptor Activation; Regulation; Relative (related person); Research Personnel; Role; Signal Transduction; Site; Stress; TLR4 gene; Time; Tissues; Transcriptional Regulation; Vagus nerve structure; Work; adipokines; authority; blood glucose regulation; energy balance; experience; glucose production; hormone regulation; inflammatory modulation; lipid biosynthesis; liver function; liver metabolism; mouse model; mutant; nerve supply; novel; obesity risk; oxysterol binding protein; programs; receptor; research study; response; sensor

The central integration of peripheral metabolic cues that lead to coordinated control of liver metabolism is very important, yet not well understood. Thus, we propose a set of projects that revolve around the general theme of peripheral inflammatory factors, such as adipokines, dietary lipids, and sex steroids, engaging key sites in the brain. These factors relay signals through autonomic and neuroendocrine outputs, thereby regulating liver function. Recently, a team of experienced investigators has coalesced at UT Southwestern that includes Phil Scherer, an expert in the area of adipocyte-derived factors, Joel Elmquist, an authority on central regulation of energy homeostasis and Deborah Clegg, bridging the CNS and adipose tissue through her studies on sex hormone regulation of obesity through modulation of inflammatory pathways. This group is complemented by the contributions of David Mangelsdorf who will closely collaborate with Joel Elmquist and will also direct a Nuclear Receptor Profiling Core that will be critical for all of the mouse models we will be producing in our studies. Joyce Repa, who will be collaborating with Phil Scherer on defining the differential transcriptional control of lipogenic pathways in adipocytes and vagal sensory neurons and Jay Horton who will direct the Metabolic Phenotyping Core. Project 1 (Scherer/Repa) will focus on the consequences of activation or inactivation of key pro-inflammatory pathways induced in adipocytes by external lipid-mediated events (via TLR4/ NFkB) on local and central mechanisms affected by altered lipid and adipokine levels. We will also take advantage of a novel function of the ER stress marker Xbp1s that allows us to potently suppress lipogenesis in an inducible fashion in both adipocytes and nodose ganglia neurons to probe the effects of lowering endogenously produced lipid pools on local inflammation. Project 2 (Elmquist/Mangelsdorf) will focus on vagal afferent neurons in the nodose ganglia that are ideally positioned to serve as a link between peripheral metabolic and inflammatory signals and the neural pathways controlling hepatic and whole body glucose homeostasis. Local PPARgamma, LXRalpha/Beta and TLR4/NFkB-mediated events in the nodose ganglia will be probed for effects on hepatic and whole body glucose homeostasis. Project 3 (Clegg/Fukuda) will focus on the anti-inflammatory properties that the estrogen receptor ERalpha exerts peripherally in adipocytes and centrally in POMC -positive neurons. Our strengths rely on the diverse expertise of the project leaders and the systematic sharing of animal models and of state-of-the- art methodologies. Combined, we feel we are uniquely positioned to address these questions that tie at the core of homeostatic control of energy homeostasis.

导致肝脏代谢协调控制的外周代谢线索的中心整合是非常重要的，但尚未得到很好的理解。因此，我们提出了一系列围绕外周炎症因子（如脂肪因子、膳食脂质和性类固醇）这一主题的项目，这些炎症因子与大脑中的关键部位有关。这些因子通过自主神经和神经内分泌输出传递信号，从而调节肝功能。 最近，一个经验丰富的研究人员团队已经在UT西南部合并，其中包括Phil谢勒，脂肪细胞衍生因子领域的专家，Joel Elmquist，能量稳态的中央调节权威和Deborah Clegg，通过她对肥胖的性激素调节的研究，通过炎症通路的调节，桥接CNS和脂肪组织。这个小组得到了大卫曼格尔斯多夫的补充，他将与乔尔·埃尔姆奎斯特密切合作，并将指导一个核受体分析核心，这对我们将在研究中生产的所有小鼠模型都至关重要。Joyce Repa将与Phil谢勒合作，定义脂肪细胞和迷走神经感觉神经元中脂肪生成途径的差异转录控制，Jay Horton将指导代谢表型核心。项目1（谢勒/Repa）将重点关注外部脂质介导事件（通过TLR 4/NF κ B）在脂肪细胞中诱导的关键促炎通路的激活或失活对受脂质和脂肪因子水平改变影响的局部和中枢机制的影响。我们还将利用ER应激标志物Xbp 1 s的一种新功能，该功能使我们能够以诱导方式有效抑制脂肪细胞和结状神经节神经元中的脂肪生成，以探索降低内源性产生的脂质池对局部炎症的影响。项目2（Elmquist/Mangelsdorf）将重点关注结状神经节中的迷走传入神经元，这些神经元理想地定位为外周代谢和炎症信号与控制肝脏和全身葡萄糖稳态的神经通路之间的联系。将探讨结状神经节中局部PPARgamma、LXR α/β和TLR 4/NF κ B介导的事件对肝脏和全身葡萄糖稳态的影响。项目3（Clegg/Fukuda）将关注雌激素受体ER α在脂肪细胞外周和POMC阳性神经元中枢发挥的抗炎特性。我们的优势依赖于项目负责人的多样化专业知识以及动物模型和最先进方法的系统共享。结合起来，我们觉得我们处于独特的位置来解决这些问题，这些问题是能量稳态的稳态控制的核心。