Adipose Tissue Carbonylome and Sustained Calorie Restriction

在没有营养不良的情况下限制热量可以延长许多物种的寿命。卡路里限制（CR）的一个标志是胰岛素敏感性。减少能量摄入长期效应的综合评估（CALARIE）研究表明，即使在经历CR的非肥胖个体中也会发生胰岛素敏感性增强， 它可能是CR发现的各种积极健康益处的关键贡献者。一般而言，在几项研究中，CR通过降低氧化应激、恢复脂肪细胞中的GLUT 4水平，从而改善全身葡萄糖处置，改善全身外周胰岛素敏感性。然而，关于这在人类中如何发生的分子机制知之甚少。与胰岛素抵抗相关的一个重要属性是氧化应激，其可导致产生反应性醛，如4-羟基壬烯醛（4-HNE），其可与蛋白质相互作用并改变其功能。新出现的证据表明，当蛋白质是GLUT 4时，葡萄糖转运通道附近的共价修饰（羰基化）就是这样一个因素，它转化为胰岛素抵抗。这些研究是我们的中心假设的基础，该假设指出改善胰岛素敏感性的机制是减少羰基应激和减轻GLUT 4羰基化。我们将通过测定持续CR受试者脂肪组织中GLUT 4羰基化的化学计量来检验这一高风险和高回报假设，并与自由进食组进行比较。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。我们还旨在评估持续CR对脂肪组织整体羰基组的影响。总之，拟定研究旨在实现PA-18-824的目标，即“鼓励进行分析，以更详细地了解热量限制（CR）对慢性疾病风险因素的影响，以及介导人类持续CR效应的细胞/分子机制”。

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.”