Novel Mechanisms Regulating the Adipocyte-Brain Hepatocyte Axis

调节脂肪细胞-脑肝细胞轴的新机制

基本信息

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
项目类别：
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

项目摘要

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.

外周代谢线索的核心整合导致对肝代谢的协调控制非常重要，但尚不清楚。因此，我们提出了一组项目，围绕外周炎症因素的一般主题，例如脂肪因子，饮食脂质和性类固醇，吸引了大脑中的关键部位。这些因素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，一组经验丰富的调查人员在UT西南航空结成了合并，其中包括菲尔·谢勒（Phil Scherer），菲尔·谢勒（Phil Scherer）是脂肪细胞衍生的因素领域的专家乔尔·埃尔姆奎斯特（Joel Elmquist），乔尔·埃尔姆奎斯特（Joel Elmquist）是对能量体内稳态的中心调节的权力，以及通过对性荷尔蒙调节性肥胖型通过模型的肥皂调节的研究来弥合CNS和脂肪组织，并通过模型进行了肥大态度。大卫·曼格尔斯多夫（David Mangelsdorf）的贡献得到了补充，戴维·曼格尔德夫（David Mangelsdorf）将与乔尔·埃尔姆奎斯特（Joel Elmquist）紧密合作，还将指导一个核受体分析核心，这对于我们研究中我们将产生的所有老鼠模型至关重要。乔伊斯·雷帕（Joyce Repa）将与菲尔·谢勒（Phil Scherer）合作，以定义脂肪细胞和迷走性感觉神经元中脂肪生成途径的差异转录控制以及将指导代谢表型核心的杰伊·霍顿（Jay Horton）。项目1（Scherer/ RepA）将重点介绍由外部脂质介导的事件（通过TLR4/ NFKB）激活或灭活脂肪细胞中关键的促炎途径对局部和中心机制受脂质变化和脂肪的影响。我们还将利用ER应力标记XBP1的新功能，使我们能够在脂肪细胞和Nodose神经元中以诱导方式有效抑制脂肪形成，以探测降低内源性产生的脂质池对局部炎症的影响。项目2（Elmquist/Mangelsdorf）将重点关注淋巴结神经节中的迷走神经神经元，理想地定位为周围代谢和炎症信号与控制肝和全身葡萄糖稳态的神经途径之间的联系。将探测局部ppargamma，lxralpha/beta和TLR4/NFKB介导的事件，探测对肝和全身葡萄糖稳态的影响。项目3（Clegg/Fukuda）将重点关注雌激素受体Eralpha外周在脂肪细胞中施加的抗炎特性，并在POMC阳性神经元中集中施加。我们的优势取决于项目领导者的多样化专业知识以及动物模型和最先进方法论的系统共享。结合在一起，我们觉得我们在解决这些问题的核心控制能量稳态的核心方面处于独特状态。