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：
8308565
负责人：
PHILIPP E SCHERER
金额：
$ 151.09万
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/8308565
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.

导致肝脏代谢协调控制的外周代谢线索的中央整合非常重要，但尚未得到充分理解。因此，我们提出了一系列围绕外周炎症因子（例如脂肪因子、膳食脂质和性类固醇）的总体主题的项目，涉及大脑的关键部位。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，德克萨斯大学西南医学中心联合了一支由经验丰富的研究人员组成的团队，其中包括脂肪细胞衍生因子领域的专家 Phil Scherer、能量稳态中央调节领域的权威 Joel Elmquist 和通过连接中枢神经系统和脂肪组织的 Deborah Clegg。她的研究是通过调节炎症途径来调节肥胖的性激素。该小组得到了 David Mangelsdorf 的补充，他将与 Joel Elmquist 密切合作，还将指导核受体分析核心，这对于我们将在研究中生产的所有小鼠模型至关重要。 Joyce Repa 将与 Phil Scherer 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，而 Jay Horton 将指导代谢表型核心。项目 1 (Scherer/Repa) 将重点关注外部脂质介导事件（通过 TLR4/NFkB）在脂肪细胞中诱导的关键促炎途径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 应激标记 Xbp1s 的新功能，该功能使我们能够以可诱导的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，以探讨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神经传入神经元，这些神经元非常适合充当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、LXRalpha/Beta 和 TLR4/NFkB 介导的事件对肝脏和全身葡萄糖稳态的影响。项目 3（Clegg/Fukuda）将重点研究雌激素受体 ERalpha 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元化专业知识以及动物模型和最先进方法的系统共享。总而言之，我们认为我们具有独特的优势来解决这些与能量稳态控制核心相关的问题。