Novel Mechanisms Regulating the Adipocyte-Brain Hepatocyte Axis

描述(申请人提供)：导致肝脏代谢协调控制的外周代谢信号的中心整合是非常重要的，但还没有被很好地理解。因此，我们提出了一套围绕外周炎症因子的总体主题的项目，如脂肪因子、膳食脂肪和性类固醇，涉及大脑中的关键部位。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，德克萨斯大学西南分校的一组经验丰富的研究人员联合起来，其中包括脂肪细胞衍生因子领域的专家Phil Scherer，能量稳态中央调节方面的权威Joel Elmquist，以及Deborah Clegg，通过她对通过调节炎症途径调节肥胖的性激素调节的研究，将中枢神经系统和脂肪组织联系起来。这个小组得到了David Mangelsdorf的补充，他将与Joel Elmquist密切合作，并将指导一个核受体分析核心，这将对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感觉神经元中造脂途径的差异转录控制，Jay Horton将领导新陈代谢表型核心。项目1(Scherer/Repa)将集中于由外部脂质介导的事件(通过TLR4/NFKB)诱导的脂肪细胞中关键的促炎通路的激活或失活对局部和中枢机制的影响，这些机制受到脂质和脂肪因子水平的影响。我们还将利用内质网应激标记Xbp1s的一种新功能，使我们能够以诱导的方式有效地抑制脂肪细胞和结状神经节神经元的脂肪生成，以探索降低内源性产生的脂类对局部炎症的影响。项目2(Elmquist/Mangelsdorf)将专注于结状神经节中的迷走神经传入神经元，这些神经元是连接外周代谢和炎症信号以及控制肝脏和全身葡萄糖稳态的神经通路的理想位置。将探讨结状神经节中局部PPARy、LXRo/p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(克莱格/福田)将专注于雌激素受体时代在外围脂肪细胞和中枢POMC阳性神经元中发挥的抗炎特性。我们的优势依赖于项目负责人的不同专业知识，以及系统地分享动物模型和最先进的方法。总而言之，我们认为我们处于独特的地位，可以解决这些问题，这些问题联系在能量平衡的平衡控制的核心。

DESCRIPTION (provided by applicant): 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 PPARy, LXRo/p and TLR4/NFKBmediated 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 ERa 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.