Methionine Aminopeptidase 2 Regulates Lipid Metabolism in Peripheral Tissues

项目摘要 肥胖是一种慢性的、反复发作的渐进性疾病过程的结果，该过程已成为一种全球流行病。 体重减少5%-10%大大有助于减少肥胖的并存，无论体重 损失是极其难以维持的。减肥药物有望成为帮助克服肥胖的干预手段 保持减肥的挑战，但由于严重的副作用，大多数已被停用。为了这个 因此，需要对产生持续减肥的策略进行进一步研究。目前有一种药物类别 在临床试验中，蛋氨酸氨基肽酶2(MetAP2)抑制剂能迅速减轻体重， 加强血糖控制，降低血脂。值得注意的是，MetAP2i的临床试验正在进行中 尽管我们对MetAP2如何介导抗肥胖作用知之甚少。体外研究表明 研究表明，MetAP2是一种多功能蛋白质，它可以从新的蛋白质中去除N端的蛋氨酸残基。 翻译的蛋白质，但也可以直接影响主要的细胞信号通路。在过去，它一直是 在体内研究MetAP2表达的影响具有挑战性，因为MetAP2的发育模式 淘汰对胚胎来说是致命的。为了克服这个问题，我们生成了鼠标模型 以可诱导的、组织特异性的方式过表达或击倒MetAP2。这些鼠标模型可以让我们 检测两种主要外周组织中MetAP2表达的系统效应和分子机制 肥胖时调节糖脂代谢的器官：肝脏和脂肪组织。仅在之后 了解MetAP2细胞效应背后的机制，我们将开始了解如何 MetAP2或MetAP2抑制剂参与全身能量平衡的复杂调节。具体而言，在 目的1我们将确定脂肪细胞和肝细胞中MetAP2的表达是否调节体重， 能量消耗、糖耐量和血脂水平。目标2的目标是检查 在体外发现的三种已知的MetAP2机制与肝脏和脂肪组织的脂质有关 体内代谢。

Project Summary Obesity is the result of a chronic, relapsing progressive disease process that has become a global pandemic. Reductions in weight as small as 5-10% drastically help reduce the comorbidities of obesity, however weight loss is extremely difficult to maintain. Anti-obesity drugs are promising interventions to help overcome the challenge of maintaining weight loss, yet most have been withdrawn due to serious side effects. For this reason, further research is needed on strategies for producing sustained weight loss. One drug class currently being tested in clinical trails, methionine aminopeptidase 2 (MetAP2) inhibitors, rapidly reduce body weight, increase glycemic control, and reduce serum lipids. Remarkably, clinical trials with MetAP2i are ongoing despite the fact we know little about how MetAP2 mediates anti-obesogenic effects. In vitro studies have shown that MetAP2 is a multifunctional protein that removes the N-terminal methionine residue from newly translated proteins, but can also directly impact major cell signaling pathways. In the past, it has been challenging to study the effects of MetAP2 expression in vivo, because the developmental models of MetAP2 elimination are embryonically lethal. To overcome this problem, we have generated mouse models that overexpress or knockdown MetAP2 in an inducible, tissue-specific manner. These mouse models will allow us to examine the systemic effects and molecular mechanisms of MetAP2 expression in two major peripheral organs that regulate glucose and lipid metabolism during obesity: liver and adipose tissue. Only after understanding the mechanisms that underlie the cellular effects of MetAP2, will we begin to understand how MetAP2 or MetAP2 inhibitors take part in the complex regulation of whole-body energy balance. Specifically, in Aim 1 we will determine whether MetAP2 expression in adipocytes and hepatocytes regulate body weight, energy expenditure, glucose tolerance, and serum lipid levels. The goal of Aim 2 is to examine whether the three known MetAP2 mechanisms discovered in vitro are found to be relevant to liver and adipose tissue lipid metabolism in vivo.