PPARdelta and its co-regulators 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性疾病。我们最近证明了核受体PPAR?？是一个关键的调节脂肪燃烧通过激活多个，协调代谢程序参与能量消耗。重要的是，我们和其他人已经证明，用PPAR治疗野生型小鼠，激动剂可预防高脂肪饮食引起的肥胖和胰岛素抵抗，表明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确定PPAR的生理作用？？在棕色脂肪代谢和确定关键的分子调控机制，用于调节其功能。在第一个目标中，我们将同时使用PPAR？缺乏棕色脂肪细胞和脂肪特异性PPAR?？敲除小鼠来确定PPAR?？棕色脂肪细胞的基础氧化代谢和能量解耦都需要PPAR?？需要做什么？-肾上腺素能受体刺激的产热，以及脂肪特异性PPAR?？对抵抗肥胖很重要。在第二个目标中，我们将确定PPAR的遗传和生化相互作用？？和辅激活剂PGC-1?？棕色脂肪。我们将检查棕色脂肪细胞中PPAR?？雇佣PGC-1 ? ?作为其主要辅激活因子，以及PGC-1的代谢功能是否至少部分是由PPAR介导的。在第三个目标中，我们将表征一种转录辅助因子的代谢功能，我们最近确定该因子是PGC-1 /PPAR的真正调节剂。-调节氧化代谢途径。我们将研究该因子与PGC-1在物理和功能上的相互作用。和PPAR ?。我们将产生在脂肪组织中表达该因子的转基因小鼠，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.