Role of perilipin in lipolysis and energy metabolism

描述(由申请人提供)：调节细胞和组织中脂肪的储存和分解(脂解)对于理解肥胖至关重要。Perilipin(PERI)蛋白被包裹在脂肪细胞内的脂滴上，被认为是脂肪储存和分解的关键调节因子，因为它们抑制脂肪分解，在没有PERI的情况下，允许发生更大的结构性脂肪分解。Peri Null(基因敲除或KO)小鼠不表达Perilipin，对饮食诱导的肥胖(DIO)具有抵抗力，并且缺乏异位脂肪。肥胖和胰岛素抵抗与脂肪分解和循环脂肪酸(FA)增加有关。FA刺激啮齿动物棕色脂肪组织(BAT)中解偶联蛋白-1(UCP1)的活性，从而以FA为代价产生热量。我们假设，这些缺失区小鼠对DIO具有抵抗力，这是由于结构性脂解作用增强，导致FA流向BAT的增加和UCPI的激活。此外，我们假设通过UCP1增加FA的代谢将保护小鼠免受胰岛素抵抗。PERI被环磷酸腺苷依赖的蛋白激酶A(PKA)磷酸化，从而取消了它对脂肪酶的抑制作用。我们已经建立了自己的PERI缺失小鼠来阐明PERI的作用，并进行了体内研究，以确定PERI和UCP1在调节能量代谢和脂肪细胞生物学中的关键作用。这些研究将帮助我们了解PERI在肥胖及其相关并发症(如糖尿病)中的潜在重要作用。

DESCRIPTION (provided by applicant): Regulation of fat storage and breakdown (lipolysis) in cells and tissues is critical to understanding obesity. Perilipin (peri) proteins, which coat the intracellular lipid droplet in adipocytes, are thought to be critical regulators of fat storage and breakdown since they inhibit lipolysis and in the absence of peri, allow for greater constitutive lipolysis to occur. Peri null (knockout or KO) mice, which do not express perilipin, are resistant to diet-induced obesity (DIO) and lack ectopic fat. Obesity and insulin resistance is associated with increased lipolysis and circulating fatty acids (FA). FA stimulate uncoupling protein-1 (UCP1) activity in the brown adipose tissue (BAT) of rodents resulting in the generation of heat at the expense of the FA. We hypothesize those peri null mice are resistant to DIO due to enhanced constitutive lipolysis, resulting in increased FA flux to BAT and activation of UCPI. Also, we hypothesize that increased metabolism of FA via UCP1 will protect the mice from becoming insulin resistant. The phosphorylation of peri by cyclic-AMP dependent protein kinase A (PKA) abrogates its inhibitory actions on lipases. We have generated our own peri null mice to elucidate peri's actions and in vivo studies to define the critical role of peri and UCP1 in modulating energy metabolism and adipocyte biology. These studies will help us to understand the potentially important role of peri in obesity and its associated complications such as diabetes.