Adipose Tissue Carbonylome and Sustained Calorie Restriction

脂肪组织羰基化和持续热量限制

基本信息

批准号：
9807394
负责人：
SALIM MERALI
金额：
$ 23.78万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9807394
关键词：
4 hydroxynonenal Acute Address Adipocytes Adipose tissue Affect Aging Aldehydes Blood Coagulation Disorders Caloric Restriction Cells Chronic Disease Cysteine Data Databases Development Dyslipidemias Energy Intake Fibrinolysis GLUT4 gene Glucose Transporter Goals Health Health Benefit Health Promotion Histidine Human Hypertension Individual Insulin Insulin Resistance Label Lead Link Lipid Peroxidation Long-Term Effects Longevity Lysine Malnutrition Mediating Modification Molecular Molecular Conformation Myocardial Infarction NIH Program Announcements Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Overnutrition Oxidative Stress Peripheral Peripheral arterial disease Physiological Post-Translational Protein Processing Process Production Proteins Proteomics Research Risk Factors Role Seminal Signal Pathway Signal Transduction Stress Stroke Testing Transducers Translating adduct age effect combat design feeding glucose disposal glucose transport healthspan high reward high risk improved insulin sensitivity men multiple reaction monitoring polypeptide stoichiometry therapeutic target western diet

项目摘要

Caloric restriction without malnutrition improves lifespan in many species. A hallmark of calorie restriction (CR) is insulin sensitivity. The Comprehensive Assessment of the Long-Term Effects of Reducing Intake of Energy (CALARIE) studies have shown that enhanced insulin sensitivity occurs even in non-obese individuals who undergo CR, and it is likely a crucial contributor to various positive health benefits found with CR. In general, across several studies, CR improves systemic peripheral insulin sensitivity by reducing oxidative stress, restoring GLUT4 levels in adipocytes, and thus improving whole-body glucose disposal. However, the molecular mechanism on how this occurs in human is poorly understood. A significant attribute associated with insulin resistance is oxidative stress, which can lead to the production of reactive aldehydes such as 4-hydroxynonenal (4-HNE), that can interact with proteins and alter their function. Emerging evidence suggests that when the protein is GLUT4, a covalent modification (carbonylation) near the glucose transport channel represents just such a factor, which translates to insulin resistance. These studies are the basis of our central hypothesis, which states that the mechanism behind improved insulin sensitivity is reduced carbonyl stress and mitigation of GLUT4 carbonylation. We will test this high risk and high reward hypothesis by determining the stoichiometry of GLUT4 carbonylations in adipose tissue of subjects on sustained CR and compare to a group fed ad libitum. We will then correlate this data to several insulin sensitivity and oxidative stress parameters in the CALARIE database. We also aim to assess the effect of sustained CR on adipose tissue global carbonylome. In summary the proposed studies are designed to address the goals of PA-18-824 which “is to encourage analyses that will lead to a more detailed understanding of the effects of caloric restriction (CR) on risk factors for chronic diseases, as well as, the cellular/molecular mechanisms mediating the effects of sustained CR in humans.”

减少能量摄入的长期影响的综合评估 (CALARIE) 研究表明，即使在非营养不良的情况下，热量限制 (CR) 的一个标志是胰岛素敏感性也会增强。 -接受 CR 的肥胖人士，以及它可能是 CR 带来的各种积极健康益处的关键因素。总的来说，多项研究表明，CR 通过减少氧化应激、恢复脂肪细胞中的 GLUT4 水平来改善全身外周胰岛素敏感性，从而改善全身葡萄糖的处理。与胰岛素抵抗相关的一个重要特征是氧化应激，它可能导致反应性醛类的产生，例如 4-羟基壬烯醛 (4-HNE)，但我们对这种情况如何在人类中发生的分子机制知之甚少。新的证据表明，当蛋白质为 GLUT4 时，葡萄糖转运通道附近的共价修饰（羰基化）就代表了这样一个因素，这会转化为胰岛素抵抗。假设，该假设指出改善胰岛素敏感性背后的机制是减少羰基应激和减轻 GLUT4 羰基化，我们将通过确定脂肪组织中 GLUT4 羰基化的化学计量来测试这一高风险和高回报的假设。然后，我们将这些数据与 CALARIE 数据库中的几个胰岛素敏感性和氧化应激参数相关联。摘要拟议的研究旨在实现 PA-18-824 的目标，即“鼓励进行分析，从而更详细地了解热量限制 (CR) 对慢性病危险因素的影响，以及，这介导人类持续 CR 影响的细胞/分子机制。”