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：
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
项目类别：
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

项目摘要

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（由适用提供）：外周代谢线索的中心整合，导致对肝脏和脂肪组织代谢的协调控制非常重要，但尚不清楚。这是我们提出的一组项目，这些项目围绕着周围代谢物（例如脂质和尿苷）的敏感性的一般主题。一组经验丰富的调查人员团队在UT Southwestern合并，其中包括Phil Scherer，Phil Scherer是脂肪细胞衍生的因素领域的专家Joel Elmquist，Joel Elmquist是对能量体内稳态中心调节的权威，以及Jay Horton，通过对Hepatiti Lipid lipid lipid的研究桥接CNS和脂肪组织。该团队与我们的核心总监Syann Lee和Ruth Gordillo一起回顾了5年的成功合作努力。项目1（Scherer）将重点关注脂肪细胞和肝细胞中细胞尿苷的生物合成的后果，通过消除和过表达尿苷产生的关键酶促机械。鉴于对肝脏（Horton）和脂肪细胞（Scherer）之间重要的代谢适应性，这是高度相关的，该转录因子由转录因子XBP1支配，该因子也由大脑（Elmquist）中发挥重要功能。将对禁食诱导的血浆尿苷对瘦素信号传导的影响（ELMQUIST）的影响进行详细评估，并将对Toll样受体4和CD36参与的研究对XBP1在多个时间中的激活（Elmquist，Horton，Scherer）进行多种时间激活。项目2（Elmquist）将详细检查迷走神经元中的脂肪酸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，从而降低了局部malonyl-COA水平。通过在POMC和/或AGRP神经元中删除脂肪酸合酶（FAS）的完整方法，导致丙二酰-COA上调，Elmquist将探测对白色脂肪组织（与Scherer）和肝素胰岛素敏感性（具有Horton）（具有Horton）的褐色影响。项目3（Horton）着重于在AGPAT2 NULL小鼠的上下文中衍生自肝脏和/或脂肪细胞的脂肪毒性信号。这些小鼠是先天性脂肪营养不良的出色模型系统，反映了AGPAT2缺乏症的临床表现，例如胰岛素抵抗，NAFLD和脂肪营养不良。霍顿（Horton）将专注于该模型中正在发挥作用的新型，规定的转录转录激活剂，并特别测试该模型中观察到的明显的神经酰胺积累是否是他还将通过与Schererants Inctign Models of函数模型的诱导性增益和与SCHERERAER合作的功能模型的诱导性增益和丧失。我们的优势依赖于项目负责人的潜水专业知识，动物模型的系统共享以及这三个项目之间的紧密交织主题方法。