Novel Mechanisms Regulating the Adipocyte-Brain-Hepatocyte Axis

 描述（由申请人提供）：导致肝脏和脂肪组织代谢协调控制的外周代谢线索的中心整合非常重要，但尚未得到充分理解。因此，我们提出了一套围绕外周代谢物（如脂质和尿苷）传感的一般主题的项目。一组经验丰富的研究人员已经在UT西南部合并，其中包括菲尔谢勒，在脂肪细胞衍生因子领域的专家，乔尔Elmquist，对能量稳态和杰伊霍顿的中央调节权威，通过他对肝脏脂质代谢的研究，桥接中枢神经系统和脂肪组织。该团队回顾了5年来在正在进行的计划项目下与我们的核心董事Syann Lee和Ruth Gordillo的成功合作。项目1（谢勒）将集中于通过消除和过表达尿苷生产的关键酶机制来操纵脂肪细胞和肝细胞中的细胞尿苷生物合成的后果。鉴于肝脏（Horton）和脂肪细胞（谢勒）之间对进食/禁食周期的重要代谢适应，这是高度相关的，主要由转录因子Xbp 1 s控制，该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增加对瘦素信号传导的影响进行详细评估（Elmquist），并将对Toll样受体4和CD 36参与多个组织中Xbp 1激活进行研究（Elmquist，Horton，谢勒）。项目2（Elmquist）将详细研究迷走神经感觉神经元中的脂肪酸摄取或合成是否通过操纵CD 36和ACC 1水平来调节肝脏（Horton）和脂肪细胞（谢勒）中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酶（FAS）导致丙二酰辅酶A上调的补充方法中，Elmquist将探索对白色脂肪组织（使用谢勒）和肝脏胰岛素敏感性（使用霍顿）的布朗宁的影响。项目3（Horton）关注在AGPAT 2缺失小鼠的背景下源自肝脏和/或脂肪细胞的脂毒性信号。这些小鼠作为先天性脂肪营养不良的优良模型系统，反映了AGPAT 2缺乏的临床表现，如胰岛素抵抗、NAFLD和脂肪营养不良。Horton将专注于在该模型中发挥作用的脂肪生成的新型非常规转录激活因子，并特别测试在该模型中观察到的突出神经酰胺积累是否是代谢失调的原因。他还将与谢勒密切合作，通过诱导性功能获得和丧失模型，仔细剖析肝脏与脂肪细胞AGPAT 2活性的相对贡献。我们的优势依赖于项目负责人的多样化专业知识，动物模型的系统共享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.