PPARdelta and its co-regulators in energy metabolism

PPARδ 及其在能量代谢中的协同调节因子

• 批准号: 8233509
• 负责人: Yong-Xu Wang
• 金额: $ 31.85万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-05 至 2013-05-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233509
• 关键词: Adipocytes; Adipose tissue; Adrenergic Receptor; Agonist; Biochemical; Biogenesis; Biological Assay; Brown Fat; Burn injury; C-terminal; Cell Nucleus; Cell Respiration; Cell surface; Dependency; Diet; Electron Transport; Energy Metabolism; Event; Exhibits; Expenditure; Fatty Acids; Fatty acid glycerol esters; Gene Targeting; Genes; Genetic; Genetic Transcription; Glucose Intolerance; Goals; Histocompatibility Testing; Insulin Resistance; Knockout Mice; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Nuclear Receptors; Obesity; PPAR delta; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Physiological; Play; Process; Proteins; Receptor Signaling; Regulation; Reporter; Research; Resistance; Role; Site; Testing; Therapeutic; Thermogenesis; Transgenic Mice; Wild Type Mouse; Work; base; bone; cell type; chromatin immunoprecipitation; fatty acid oxidation; gain of function; in vivo; lipid biosynthesis; lipid metabolism; overexpression; oxidation; prevent; programs; promoter; transcription factor

DESCRIPTION (provided by applicant): Our long-term goal is to understand the transcription basis of energy metabolism and how the involved transcriptional pathways contribute to metabolic diseases. We have recently demonstrated that nuclear receptor PPAR??is a key regulator for fat burning by activating multiple, coordinated metabolic programs involved in energy expenditure. Importantly, we and others have shown that treatment of wild-type mice with the PPAR??agonist prevents high-fat diet induced obesity and insulin resistance, indicating potential therapeutic values of the agonist for the treatment of metabolic diseases. Our current focus is to determine in detail the physiological role of PPAR??in brown fat metabolism and identify the key molecular regulatory mechanisms that are used to regulate its function. In the first aim, we will use both PPAR?-deficient brown fat cells and fat-specific PPAR??knockout mice to determine whether PPAR??is required for both basal oxidative metabolism and energy uncoupling in brown fat cells, whether PPAR??is required for ?-adrenergic receptor-stimulated thermogenesis, and whether fat-specific PPAR??is important to obesity resistance. In the second aim, we will determine the genetic and biochemical interactions of PPAR??and co-activator PGC-1??in brown fat. We will examine whether in brown fat cells PPAR??employs PGC-1??as its major coactivator and whether the metabolic function of PGC-1??is mediated, at least in part, by PPAR?. In the third aim, we will characterize the metabolic function of a transcriptional co-factor that we have recently identified as a bona fide modulator for PGC-1?/PPAR?- regulated oxidative metabolism pathway. We will examine the physical and functional interactions of this factor with PGC-1??and PPAR?. We will generate transgenic mice expressing this factor in adipose tissue to analyze its in vivo role in energy metabolism.

描述（由申请人提供）：我们的长期目标是了解能量代谢的转录基础以及所涉及的转录途径如何导致代谢疾病。我们最近证明，核受体 PPAR 通过激活涉及能量消耗的多个协调代谢程序，成为脂肪燃烧的关键调节剂。重要的是，我们和其他人已经证明，用PPAR激动剂治疗野生型小鼠可以预防高脂饮食引起的肥胖和胰岛素抵抗，这表明该激动剂对于治疗代谢疾病具有潜在的治疗价值。我们当前的重点是详细确定 PPAR 在棕色脂肪代谢中的生理作用，并确定用于调节其功能的关键分子调节机制。在第一个目标中，我们将使用 PPAR？缺乏的棕色脂肪细胞和脂肪特异性 PPAR？敲除小鼠来确定 PPAR？是否是棕色脂肪细胞中基础氧化代谢和能量解偶联所必需的。 α-肾上腺素能受体刺激的生热作用需要α-肾上腺素能受体，并且脂肪特异性PPARα对于抵抗肥胖是否很重要。第二个目标是确定棕色脂肪中 PPAR 和共激活剂 PGC-1 的遗传和生化相互作用。我们将检查棕色脂肪细胞中的 PPAR 是否使用 PGC-1 作为其主要共激活剂，以及 PGC-1 的代谢功能是否至少部分由 PPAR 介导。在第三个目标中，我们将表征转录辅助因子的代谢功能，我们最近将其确定为 PGC-1?/PPAR? 调节的氧化代谢途径的真正调节剂。我们将研究该因子与 PGC-1 和 PPAR 的物理和功能相互作用。我们将产生在脂肪组织中表达该因子的转基因小鼠，以分析其在能量代谢中的体内作用。