Role of perilipin in lipolysis and energy metabolism

描述（由申请人提供）：细胞和组织中脂肪储存和分解（脂解）的调节对于理解肥胖至关重要。包被在脂肪细胞中的细胞内脂滴的周脂蛋白（Perilipin，PPL）蛋白被认为是脂肪储存和分解的关键调节剂，因为它们抑制脂解，并且在不存在PPL的情况下，允许发生更大的组成性脂解。不表达围脂蛋白的围脂基因敲除（敲除或KO）小鼠对饮食诱导的肥胖症（DIO）具有抗性并且缺乏异位脂肪。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（UCP 1）的活性，导致以FA为代价产生热量。我们假设这些β-D受体缺失小鼠由于增强的组成性脂解而对DIO具有抗性，从而导致FA向BAT的通量增加和UCPI的激活。此外，我们假设通过UCP 1增加FA的代谢将保护小鼠免受胰岛素抵抗。环腺苷酸依赖性蛋白激酶A（cyclic-AMP dependent protein kinase A，PKA）可使其磷酸化，从而消除其对脂肪酶的抑制作用。我们已经产生了我们自己的UCP 1基因敲除小鼠来阐明UCP 1的作用，并进行了体内研究来确定UCP 1和UCP 1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.