Novel Mechanisms Regulating the Adipocyte-Brain-Hepatocyte Axis

 描述(申请人提供)：导致肝脏和脂肪组织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，我们提出了一系列围绕感知外周代谢物(如脂质和尿苷)的总主题的项目。德州大学西南分校联合了一组经验丰富的研究人员，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和通过其对肝脂代谢的研究连接中枢神经系统和脂肪组织的Jay Horton。本团队与我们的核心总监Syann Lee和Ruth Gordillo一起回顾了正在进行的计划项目下5年来成功的合作努力。项目1(Scherer)将专注于通过消除和过度表达尿苷产生的关键酶机制来操纵脂肪细胞和肝细胞中细胞尿苷生物合成的后果。鉴于肝脏(Horton)和脂肪细胞(Scherer)之间的摄食/禁食周期的重要代谢适应，这一点高度相关，主要由转录因子Xbp1s控制，该转录因子也在大脑中发挥重要功能(Elmquist)。将对禁食诱导的血浆尿苷升高对瘦素信号的影响(Elmquist)进行详细评估，并将对Toll样受体4和CD36在多个组织中对Xbp1s激活的参与进行研究(Elmquist，Horton，Scherer)。项目2(Elmquist)将详细研究迷走感觉神经元对脂肪酸的摄取或合成是否通过操纵CD36和ACC1水平来调节肝脏(Horton)和脂肪细胞(Scherer)的能量平衡和葡萄糖稳态，从而降低局部丙二酰辅酶A水平。在通过缺失POMC和/或AgRP神经元中的脂肪酸合成酶(Fas)而导致丙二酰辅酶A上调的补充方法中，Elmquist将探讨对白色脂肪组织褐化(与Scherer)和肝脏胰岛素敏感性(与Horton)的影响。项目3(Horton)专注于在AGPAT2缺失小鼠的背景下来自肝脏和/或脂肪细胞的脂毒信号。这些小鼠作为先天性脂肪营养不良的优秀模型系统，反映了AGPAT2缺乏的临床表现，如胰岛素抵抗、NAFLD和脂肪营养不良。Horton将专注于在这个模型中发挥作用的新的、非常规的脂肪生成转录激活剂，并具体测试在这个模型中观察到的显著神经酰胺堆积是否导致代谢失调。他还将与谢勒密切合作，通过可诱导的功能获得和功能丧失模型，仔细剖析肝脏和脂肪细胞AGPAT2活性的相对贡献。我们的优势依赖于项目负责人的不同专业知识，系统地分享动物模型，以及三个项目之间紧密交织的主题方法。

 DESCRIPTION (provided by applicant): The central integration of peripheral metabolic cues that lead to the coordinated control of liver and adipose tissue metabolism is very important, yet not well understood. Thus, we propose a set of projects that revolve around the general theme of sensing of peripheral metabolites, such as LIPIDS and URIDINE. 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 Jay Horton, bridging the CNS and adipose tissue through his studies on hepatic lipid metabolism. This team looks back on 5 years of successful collaborative efforts under the ongoing Program Project, together with our Core Directors Syann Lee and Ruth Gordillo. Project 1 (Scherer) will focus on the consequences of manipulating the cellular uridine biosynthesis in the adipocyte and hepatocyte by eliminating and overexpressing the key enzymatic machinery for uridine production. This is highly relevant in light of the important metabolic adaptations to the feeding/fasting cycle between the liver (Horton) and adipocytes (Scherer), governed primarily by the transcription factor Xbp1s that also exerts important functions in the brain (Elmquist). A detailed assessment will be performed on the impact of the fasting-induced plasma uridine increase on leptin signaling (Elmquist) and studies on the involvement of Toll-like receptor 4 and CD36 on the activation of Xbp1s in multiple tissues will be performed (Elmquist, Horton, Scherer). Project 2 (Elmquist) will examine in detail whether fatty acid uptake or synthesis in vagal sensory neurons regulates energy balance and glucose homeostasis in the liver (Horton) and the adipocyte (Scherer) by manipulating CD36 and ACC1 levels, thereby lowering local malonyl-CoA levels. In a complementary approach leading to an upregulation of malonyl-CoA through deletion of fatty acid synthase (FAS) in POMC and/or AgRP neurons, Elmquist will probe the impact on browning of white adipose tissue (with Scherer) and hepatic insulin sensitivity (with Horton). Project 3 (Horton) focuses on lipotoxic signals derived from livers and/or adipocytes in the context of the AGPAT2 null mouse. These mice serve as an excellent model system for congenital lipodystrophy, mirroring the clinical manifestations of AGPAT2 deficiency, such as insulin resistance, NAFLD, and lipodystrophy. Horton will focus on novel, non-conventional transcriptional activators of lipogenesis that are at play in this model, and specifically test whether the prominent ceramide accumulation observed in this model is responsible for the metabolic dysregulation. He will also carefully dissect the relative contributions of liver versus adipocyte AGPAT2 activity through inducible gain- and loss of function models in close collaboration with Scherer. Our strengths rely on the diverse expertise of the project leaders, the systematic sharing of animal models and the tightly interwoven thematic approaches amongst the three projects.