Methionine Aminopeptidase 2 Regulates Lipid Metabolism in Peripheral Tissues

项目摘要 肥胖症是一种慢性、复发性进行性疾病过程的结果，已成为全球流行病。 体重减少5-10%，大大有助于减少肥胖的合并症，但体重 亏损是很难维持的。抗肥胖药物是有希望的干预措施，以帮助克服 维持减肥的挑战，但大多数已退出由于严重的副作用。为此 因此，需要进一步研究产生持续减肥的策略。目前有一类药物 在临床试验中测试，甲硫氨酸氨基肽酶2（MetAP 2）抑制剂，迅速减轻体重， 增加血糖控制和降低血脂。值得注意的是，MetAP 2 i的临床试验正在进行中 尽管我们对MetAP 2如何介导抗肥胖作用知之甚少。体外研究 显示MetAP 2是一种多功能蛋白，其从新的细胞中去除N-末端甲硫氨酸残基， 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， 研究体内MetAP 2表达的影响具有挑战性，因为MetAP 2的发育模型 消除是胚胎致命的。为了克服这个问题，我们已经生成了小鼠模型， 以可诱导的、组织特异性的方式过表达或敲低MetAP 2。这些小鼠模型将使我们 研究MetAP 2表达在两种主要外周血淋巴细胞中的全身效应和分子机制， 在肥胖期间调节葡萄糖和脂质代谢的器官：肝脏和脂肪组织。后才 了解MetAP 2细胞效应的机制，我们将开始了解如何 MetAP 2或MetAP 2抑制剂参与全身能量平衡的复杂调节。具体到 目的1：我们将确定脂肪细胞和肝细胞中MetAP 2的表达是否调节体重， 能量消耗、葡萄糖耐量和血脂水平。目标2的目标是检查 发现体外发现的三种已知的MetAP 2机制与肝脏和脂肪组织脂质相关 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drugs are promising interventions to help overcome the challenge of maintaining weight loss, yet most have been withdrawn due to serious side effects.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.