Adipose Tissue Carbonylome and Sustained Calorie Restriction

脂肪组织羰基化和持续热量限制

• 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
• 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

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.”

无营养不良的热量限制可改善许多物种的寿命。卡路里限制（CR）的标志是胰岛素灵敏度。对减少能量摄入（Calarie）研究的长期影响的全面评估表明，即使在接受CR的非肥胖个体中，胰岛素敏感性也会增强 这可能是CR所发现的各种积极健康益处的至关重要的贡献者。通常，在几项研究中，CR通过减少氧化应激，恢复脂肪细胞中的GLUT4水平，从而改善全身葡萄糖处置，从而提高全身性周围胰岛素敏感性。但是，关于人类如何发生的分子机制知之甚少。与胰岛素耐药性相关的重要属性是氧化应激，这可能导致产生反应性醛，例如4-羟基诺烯酸（4-HNE），可以与蛋白质相互作用并改变其功能。新兴的证据表明，当蛋白质为Glut4时，葡萄糖传输通道附近的共价修饰（羰基化）仅代表了这样一个因素，它转化为胰岛素抵抗。这些研究是我们中心假设的基础，该假设指出，提高胰岛素敏感性背后的机制是羰基应力降低和缓解GLUT4羰基化的作用。我们将通过确定受试者持续CR的受试者脂肪组织中Glut4羰基化的化学计量来检验这种高风险和高奖励假设，并与饲养的征服的组相比。然后，我们将将这些数据与Calarie数据库中的几种胰岛素敏感性和氧化应激参数相关联。我们还旨在评估持续CR对脂肪组织全球羰基群的影响。总而言之，拟议的研究旨在解决PA-18-824的目标，“这是“鼓励分析，这将使对热量限制（CR）（CR）对慢性疾病的影响以及细胞/分子机制的影响更详细地理解，从而介导了CRS持续的CR的影响。”