PPAR delta functions in liver

描述(申请人提供)：过氧化物酶体增殖物激活受体(PPAR)的成员调节重要的转录程序，以维持代谢稳态，因此是目前和未来治疗代谢性疾病的靶点。我们的长期目标是了解每个代谢活跃的组织中的调节机制，PPAR是通过哪一种？(也称为PPAR？)控制新陈代谢。以前的研究表明，这种受体增加了外周组织中的脂肪酸氧化，以防止饮食诱导的肥胖。利用小鼠的胰岛素抵抗模型，我们的结果已经确定肝脏是PPAR？在调节葡萄糖和脂肪酸代谢以及胰岛素敏感性方面的作用。与其在外周的活性相比，我们发现PPAR？激活通过调节葡萄糖利用途径降低血糖水平，包括糖原和脂肪酸合成。该假说认为PPARd通过三步能量底物转换机制在控制肝脏脂肪和碳水化合物代谢中发挥重要作用，在该机制中，PPARd促进肝脏中葡萄糖的利用以合成糖原和脂肪酸。新制造的脂类随后由极低密度脂蛋白输送并在外周使用。特定的目的是为了确定PPAR？调节这些过程，这应该确定新的治疗途径，以控制代谢性疾病的进展，如胰岛素抵抗。

DESCRIPTION (provided by applicant): Members of the peroxisome proliferator-activated receptors (PPARs) regulate important transcriptional programs to maintain metabolic homeostasis and as such are current and prospective therapeutic targets to treat metabolic diseases. Our long-term goal is to understand the regulatory mechanisms in each of the metabolically active tissues through which PPAR? (also referred to as PPAR?) controls metabolism. Previous studies have suggested that this receptor increases fatty acid ?-oxidation in peripheral tissues to prevent diet-induced obesity. Using mouse models of insulin resistance, our results have identified the liver as an additional site of PPAR? action in regulating glucose and fatty acid metabolism as well as insulin sensitivity. In contrast to its activity in the periphery, we found that PPAR? activation lowers glucose levels through regulation of glucose utilization pathways, including glycogen and fatty acid synthesis. The hypothesis behind this proposal is that PPARd plays an important role in controlling hepatic lipid and carbohydrate metabolism through a three-step energy substrate switching mechanism, in which it promotes glucose utilization in liver for the synthesis of glycogen and fatty acids. The newly made lipids are subsequently delivered by VLDL and utilized in the periphery. The specific aims are designed to determine the molecular mechanisms by which PPAR? regulates these processes, which should identify novel therapeutic pathways to control the progression of metabolic diseases, such as insulin resistance.