PPARdelta and its co-regulators in energy metabolism

描述(由申请者提供)：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促进代谢性疾病。我们最近已经证明，核受体PPAR？？是脂肪燃烧的关键调节因子，它通过激活参与能量消耗的多个协调代谢程序来调节脂肪燃烧。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防止高脂饮食引起的肥胖和胰岛素抵抗，这表明这种激动剂在治疗代谢性疾病方面具有潜在的治疗价值。我们目前的重点是详细地确定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控机制。在第一个目标中，我们将使用PPAR基因缺陷的棕色脂肪细胞和脂肪特异性PPAR基因敲除小鼠来确定PPAR是否对棕色脂肪细胞的基础氧化代谢和能量解偶联都是必需的，PPAR是否是肾上腺素能受体刺激的产热所必需的，以及脂肪特异性PPAR是否对肥胖抵抗是重要的。在第二个目标中，我们将确定棕色脂肪中PPAR？和共激活因子PGC-1？的遗传和生化相互作用。我们将研究在棕色脂肪细胞中，PPAR是否使用PGC-1作为其主要的辅助激活因子，以及PGC-1的代谢功能是否至少部分地由PPAR？介导。在第三个目标中，我们将表征一个转录辅助因子的代谢功能，我们最近发现它是PGC-1/PPAR？调节氧化代谢途径的真正调节者。我们将研究该因子与PGC-1？和PPAR？的物理和功能相互作用。我们将在脂肪组织中产生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。

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.