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: 8035398
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035398
• 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，以及相关的转录途径如何导致代谢性疾病。我们最近证明，核受体过氧化物酶体增殖物激活受体？？是脂肪燃烧的关键调节剂，通过激活涉及能量消耗的多个协调代谢程序。重要的是，我们和其他人已经表明，野生型小鼠的治疗与过氧化物酶体增殖物激活受体？激动剂预防高脂饮食诱导的肥胖和胰岛素抵抗，表明激动剂用于治疗代谢性疾病的潜在治疗价值。我们目前的重点是确定详细的生理作用的过氧化物酶体增殖物激活受体？？在棕色脂肪代谢中的作用，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，我们将使用两个PPAR？-缺乏棕色脂肪细胞和脂肪特异性过氧化物酶体增殖物激活受体？？敲除小鼠，以确定是否PPAR？？是所需的基础氧化代谢和能量解偶联在棕色脂肪细胞，是否过氧化物酶体增殖物激活受体？需要什么？肾上腺素能受体刺激产热，是否脂肪特异性过氧化物酶体增殖物激活受体？？对抵抗肥胖很重要。在第二个目标，我们将确定的遗传和生化相互作用的过氧化物酶体增殖物激活受体？？和共激活剂PGC-1？棕色脂肪。我们将研究是否在棕色脂肪细胞的过氧化物酶体增殖物激活受体？使用PGC-1？？PGC-1作为其主要的共激活因子，其代谢功能是否与PGC-1的代谢功能有关？至少部分由PPAR？介导。在第三个目标中，我们将描述一个转录辅因子的代谢功能，我们最近已经确定为PGC-1？/过氧化物酶体过氧化物酶体？调节氧化代谢途径。我们将研究这个因素与PGC-1的物理和功能相互作用？所以，PPAR？我们将产生在脂肪组织中表达该因子的转基因小鼠，以分析其在体内能量代谢中的作用。