PPARdelta and its co-regulators in energy metabolism

我们的长期目标是了解能量新陈代谢的转录基础，以及参与的 转录途径导致代谢性疾病。我们最近已经证明了核子 受体PPAR6是脂肪燃烧的关键调节器，通过激活多个协调的代谢程序。 重要的是，我们和其他人已经证明，PPAR5激动剂可以防止高脂饮食诱导的肥胖和 小鼠的胰岛素抵抗，提示该激动剂治疗代谢疾病的潜在治疗价值 疾病。我们目前的重点是详细确定PPAR6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PPAR6缺陷的棕色脂肪细胞和脂肪特异的PPAR8基因敲除小鼠来确定 PPAR6是棕色脂肪细胞基础氧化代谢和能量解偶联所必需的，无论是 PPAR6是p-肾上腺素能受体刺激的产热所必需的，以及脂肪特异性PPAR5是否 对抵抗肥胖很重要。在第二个目标中，我们将确定遗传和生化 棕色脂肪中PPAR5与共激活子PGC-1a的相互作用。我们将研究PPAR5是否 使用PGC-1a作为其主要的辅助激活剂，以及PGC-1a的代谢功能是否被介导，在 至少部分是通过PPAR 5。在第三个目标中，我们将描述一种转录辅因子的代谢功能。 我们最近发现它是PGC-1cc/PPAR6调节的氧化的真正调节剂 代谢途径。我们将研究这个辅因子与PGC-1a的物理和功能相互作用。 和PPAR 8。我们将在脂肪组织中产生表达这种辅因子的转基因小鼠，以分析其在 活体在能量代谢中的作用。肥胖和相关的2型糖尿病和心血管疾病是 工业世界的严重医疗问题。能量代谢失调在很大程度上是原因 治疗这些疾病。我们的研究应该为我们提供对PPAR6及其协同调节因子的新的分子见解 在控制能量代谢方面，这显然对开发新的 治疗。

Our long-term goal is to understand the transcriptional basis of energy metabolism and how the involved transcriptional pathways contribute to metabolic diseases. We have recently demonstrated that the nuclear receptor PPAR6 is a key regulator for fat burning by activating multiple, coordinated metabolic programs. Importantly, we and others have shown that the PPAR5 agonist prevents high-fat diet induced obesity and insulin resistance in mice, 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 PPAR6 in brown fat metabolism and identify key molecular regulatory mechanisms that are used to regulate its function. In the first aim, we will use both PPAR6-deficient brown fat cells and fat-specific PPAR8 knockout mice to determine whether PPAR6 is required for both basal oxidative metabolism and energy uncoupling in brown fat cells, whether PPAR6 is required for p-adrenergic receptor-stimulated thermogenesis, and whether fat-specific PPAR5 is important for obesity resistance. In the second aim, we will determine the genetic and biochemical interactions between PPAR5 and co-activator PGC-1a in brown fat. We will examine whether PPAR5 employs PGC-1a as its major co-activator and whether the metabolic function of PGC-1a is mediated, at least in part, by PPAR5. In the third aim, we will characterize the metabolic function of a transcriptional cofactor that we recently identified as a bona fide modulator for PGC-1cc/PPAR6-regulated oxidative metabolism pathway. We will examine the physical and functional interactions of this co-factor with PGC-1a and PPAR8. We will generate transgenic mice expressing this co-factor in adipose tissue to analyze its in vivo role in energy metabolism. Obesity and associated type 2 diabetes and cardiovascular diseases are serious medical problems in the industrial world. Disregulation of energy metabolism is largely responsible for these diseases. Our studies should provide us novel molecular insights into PPAR6 and its co-regulators in control of energy metabolism, which will clearly be very useful for the development of new therapies.