Novel Mechanisms Regulating the Adipocyte-Brain-Hepatocyte Axis

调节脂肪细胞-脑-肝细胞轴的新机制

• 批准号: 9100718
• 负责人: PHILIPP E SCHERER
• 金额: $ 198.54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-22 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100718
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Afferent Neurons; Anabolism; Animal Model; Area; Back; Biological Assay; Biological Models; Body Weight decreased; Brain; CD36 gene; Cardiovascular Diseases; Ceramides; Chronic; Clinical; Collaborations; Communication; Cues; Data; Deposition; Development; Diabetes Mellitus; Dyslipidemias; Familial generalized lipodystrophy; Fasting; Fatty Acids; Fatty-acid synthase; Fibrosis; Funding; Gene Expression; Grant; Hand; Hepatic; Hepatocyte; High Fat Diet; Histology; Homeostasis; Hypothalamic structure; Hypoxia; Individual; Insulin; Insulin Resistance; Knockout Mice; Laboratories; Lead; Leptin; Light; Lipids; Lipodystrophy; Liver; Malonyl Coenzyme A; Measurement; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mind; Modeling; Molecular Biology; Mus; Nervous system structure; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Overnutrition; Pathogenesis; Pathway interactions; Perinatal; Peripheral; Phenotype; Physiological; Physiology; Plasma; Play; Process; Production; Reagent; Regulation; Research Personnel; Role; Science; Signal Transduction; TLR4 gene; Temperature; Testing; Tissues; Transcription Coactivator; Transducers; Triglycerides; Up-Regulation; Uridine; Work; adipocyte differentiation; adipokines; authority; blood glucose regulation; energy balance; experience; fatty acid-transport protein; feeding; in utero; insulin sensitivity; lipid biosynthesis; lipid metabolism; loss of function; metabolic phenotype; mouse model; non-alcoholic fatty liver; novel; overexpression; programs; public health relevance; respiratory; tool; transcription factor; uptake

 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.

 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央整合非常重要，但尚未得到很好的理解。因此，我们提出了一系列围绕以下总体主题的项目。 UT Southwestern 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 和 Joel Elmquist。能量稳态中央调节方面的权威和 Jay Horton，通过他对肝脏脂质代谢的研究将中枢神经系统和脂肪组织联系起来。该团队回顾了我们的核心董事 Syann Lee 和我们在正在进行的项目下 5 年的成功合作。 Ruth Gordillo，项目 1（Scherer）将重点关注通过消除和过度表达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。这与肝脏 (Horton) 和脂肪细胞 (Scherer) 之间的进食/禁食周期的重要代谢适应高度相关，主要由转录因子 Xbp1s 控制，该转录因子也在大脑 (Elmquist) 中发挥重要功能。将详细评估禁食引起的血浆尿苷增加对瘦素信号传导（Elmquist）的影响，并研究 Toll 样受体 4 和 CD36 对瘦素信号传导的影响。将在多个组织中激活 Xbp1（Elmquist、Horton、Scherer），项目 2 (Elmquist) 将详细检查迷走神经感觉神经元中的脂肪酸摄取或合成是否调节肝脏 (Horton) 和肝脏中的能量平衡和葡萄糖稳态。通过操纵 CD36 和 ACC1 水平，从而降低局部丙二酰辅酶 A 水平，从而导致脂肪细胞 (Scherer) 上调。 Elmquist 将通过删除 POMC 和/或 AgRP 神经元中的脂肪酸合酶 (FAS) 来研究丙二酰辅酶 A 对白色脂肪组织褐变（与 Scherer 合作）和肝脏胰岛素敏感性（与 Horton 合作）的影响。在 AGPAT2 缺失小鼠的背景下，对来自肝脏和/或脂肪细胞的脂毒性信号进行了研究，这些小鼠是先天性脂肪营养不良的优秀模型系统，反映了先天性脂肪营养不良的情况。 Horton 将关注 AGPAT2 缺陷的临床表现，例如胰岛素抵抗、NAFLD 和脂肪营养不良，重点关注在该模型中发挥作用的新型非传统脂肪生成转录激活剂，并专门测试该模型中观察到的显着神经酰胺积累是否是重要的。他还将与 Scherer 密切合作，通过诱导功能获得和丧失模型，仔细剖析肝脏脂肪细胞 AGPAT2 活性的相对贡献。项目领导者的多样化专业知识、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。