Methionine Aminopeptidase 2 Regulates Lipid Metabolism in Peripheral Tissues

蛋氨酸氨基肽酶 2 调节外周组织中的脂质代谢

• 批准号: 10388782
• 负责人: Christy M Gliniak
• 金额: $ 3.52万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388782
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; Amines; Anti-Obesity Agents; Binding Proteins; Biological Assay; Body Composition; Body Weight; Body Weight decreased; Cell Proliferation; Cells; Cellular Metabolic Process; Cholesterol; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Coronary heart disease; Data; Defect; Development; Diabetes Mellitus; Doxycycline; EIF-2alpha; Embryo; Energy Metabolism; Enzymes; Epidemic; Eukaryotic Initiation Factor-2; Excision; Fatty acid glycerol esters; Glucose; Goals; Growth; Health; Heart Diseases; Hepatocyte; Homeostasis; Human; In Vitro; Intervention; Isotope Labeling; Knock-out; Knockout Mice; Lipids; Liver; MAPK3 gene; Measures; Mediating; Medical; Metabolic; Metabolism; Methionine; Modeling; Modification; Molecular; Mus; N-terminal; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organ; Pathologic; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Inhibition; Plasma; Prevalence; Process; Progressive Disease; Proteins; Proteome; Regulation; Relapse; Research; Risk; Role; Serum; Signal Pathway; Signal Transduction; Stroke; Testing; Tissues; Translating; Triglycerides; Weight; Weight Gain; adult obesity; base; cell growth; comorbidity; endoplasmic reticulum stress; energy balance; experimental study; feeding; global health; glucose metabolism; glucose tolerance; glycemic control; improved; in vivo; inhibitor/antagonist; insulin sensitivity; knock-down; lipid metabolism; methionine aminopeptidase 2; model design; mouse model; novel; obesity treatment; obesogenic; overexpression; pandemic disease; response; side effect; weight loss intervention

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drugs are promising interventions to help overcome the challenge of maintaining weight loss, yet most have been withdrawn due to serious side effects.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.

项目概要 肥胖是一种慢性、复发性进行性疾病过程的结果，该疾病已成为全球流行病。 体重减轻小至 5-10% 就可以极大地帮助减少肥胖的合并症，但是体重 损失是极其难以维持的。抗肥胖药物是有希望的干预措施，有助于克服肥胖问题 维持减肥的挑战，但大多数已因严重的副作用而退出。为了这 因此，需要进一步研究产生持续减肥的策略。目前只有一类药物 蛋氨酸氨基肽酶 2 (MetAP2) 抑制剂正在临床试验中进行测试，可迅速减轻体重， 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 尽管事实上我们对 MetAP2 如何介导抗肥胖作用知之甚少。体外研究已 结果表明，MetAP2 是一种多功能蛋白，可去除新生成的 N 端甲硫氨酸残基。 翻译的蛋白质，但也可以直接影响主要细胞信号传导途径。过去，一直是 研究 MetAP2 体内表达的影响具有挑战性，因为 MetAP2 的发育模型 消除是胚胎致死的。为了克服这个问题，我们生成了小鼠模型 以可诱导的、组织特异性的方式过表达或敲低 MetAP2。这些鼠标模型将使我们能够 检查 MetAP2 表达在两个主要外周血中的系统效应和分子机制 肥胖期间调节葡萄糖和脂质代谢的器官：肝脏和脂肪组织。仅在之后 了解了 MetAP2 细胞作用的机制后，我们是否会开始了解如何 MetAP2 或 MetAP2 抑制剂参与全身能量平衡的复杂调节。具体来说，在 目标 1 我们将确定脂肪细胞和肝细胞中的 MetAP2 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 的目标是检查是否 体外发现的三种已知的 MetAP2 机制被发现与肝脏和脂肪组织脂质相关 体内代谢。