PPAR delta functions in liver

描述（由申请人提供）：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，因此是治疗代谢性疾病的当前和未来的治疗靶点。我们的长期目标是了解PPAR通过哪些代谢活性组织中的调节机制？（也称为PPAR?）控制新陈代谢。先前的研究表明，这种受体会增加脂肪酸？-外周组织氧化，防止饮食引起的肥胖。使用小鼠胰岛素抵抗模型，我们的研究结果已经确定肝脏是PPAR？调节葡萄糖和脂肪酸代谢以及胰岛素敏感性的作用。与它在外周的活动相反，我们发现PPAR？激活通过调节葡萄糖利用途径（包括糖原和脂肪酸合成）降低葡萄糖水平。该假说认为，PPARd通过三步能量底物转换机制，促进肝脏对葡萄糖的利用，合成糖原和脂肪酸，在控制肝脏脂质和碳水化合物代谢中发挥重要作用。新生成的脂质随后由VLDL传递并在外周利用。具体目的是确定PPAR？调节这些过程，这应该确定新的治疗途径来控制代谢疾病的进展，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.