Mechanisms underlying the effects of time-restricted feeding on lipid metabolism

项目摘要 今天，我们生活在一个前所未有的获得食物的时代。最近的研究表明，许多美国人吃 从他们醒来的时候到他们睡觉的时候。特别是夜间进食与几种衰老有关-- 相关的合并症，包括肥胖、心血管疾病和2型糖尿病。虽然很多事情都在进行中 研究人员调查了饮食成分影响新陈代谢的机制，但对其机制了解较少。 喂食的时间会影响新陈代谢。为此，改变喂食时间的饮食干预措施有 即使在不减少卡路里摄入量的情况下，也被证明可以保护健康的许多方面。限时喂食 (TRF)饮食已被证明在小鼠和人类身上可以减少氧化应激和炎症，降低胰岛素 抵抗，降低血糖。在小鼠身上，TRF已被证明可以降低脂肪水平，防止高脂饮食， 并防止肥胖。利用黑腹果蝇，Shirasu-Hiza实验室开发出一种健壮的TRF饮食， 延长寿命和延缓衰老的分子迹象，如蛋白质聚集，并表明TRF 增强昼夜节律基因的表达，并需要生物钟来赋予寿命益处。此外，我们 发现TRF似乎重新编程了脂代谢；在TRF治疗后，果蝇对禁食的反应是利用 血脂比对照组快得多，导致三酰甘油损失和饥饿敏感性增加。我 发现这种TRF加速的脂质使用，就像TRF诱导的寿命延长一样，需要昼夜节律成分 但是，与TRF诱导的寿命延长不同，它不需要自噬成分。因为潜在的 机制尚不清楚，我建议确定驱动TRF对血脂影响的分子成分 新陈代谢。我将使用果蝇，一种有利的模式生物进行这项工作，因为：许多 哺乳动物的代谢途径在果蝇身上是保守的；果蝇的世代时间很短(2-3个月)；以及果蝇 提供了过多的强大的基因工具。目标1将识别特定组织(S)，其中昼夜节律调节器 TRF加速的脂质使用所必需的。目标2将研究TRF改变的分子机制 脂类代谢。我将使用RNA测序分析来确定TRF治疗后的转录差异 苍蝇及其对照；显著差异表达的基因和/或途径将被评估 在TRF加速脂质使用中的功能作用。目标3将研究TRF在饮食中的治疗潜力- 诱导性肥胖。喂食高糖饮食并有肥胖症状的苍蝇将接受TRF治疗，以测试是否 与肥胖相关的表型在TRF治疗后得到改善；我们将同时测试幼龄和老年果蝇。这些 实验将确定TRF与脂质代谢的分子机制，以及TRF如何 用于改善肥胖和衰老相关的病理。这将提高我们对扶轮基金会如何 赋予健康寿命的好处，同时也测试其在与衰老相关的饮食诱导的肥胖症的治疗潜力。

Project Summary Today, we live in an age of unprecedented access to food. Recent research suggests that many Americans eat from the time they wake up to the time they go to sleep. Night eating, specifically, is linked to several aging- related comorbidities, including obesity, cardiovascular disease, and type-2 diabetes. While much ongoing research investigates the mechanisms by which dietary components affect metabolism, it is less understood how the timing of feeding affects metabolism. To this end, dietary interventions that alter the timing of feeding have been shown to protect many aspects of health, even without reducing caloric intake. Time-restricted feeding (TRF) diets have been shown in mice and humans to reduce oxidative stress and inflammation, decrease insulin resistance, lower blood sugar. In mice, TRF has been shown to reduce fat levels, protect against a high-fat diet, and prevent obesity. Using Drosophila melanogaster, the Shirasu-Hiza lab developed a robust TRF diet that extends lifespan and delays molecular signs of aging, such as protein aggregation, and showed that TRF enhances circadian gene expression and requires the circadian clock to confer lifespan benefits. In addition, we found that TRF seems to reprogram lipid metabolism; after TRF treatment, flies responded to fasting by utilizing lipids much faster than controls, leading to increased rate of triacylglyceride loss and starvation sensitivity. I found that this TRF-accelerated lipid usage, like TRF-induced lifespan extension, requires circadian components but, unlike TRF-induced lifespan extension, does not require autophagy components. Because the underlying mechanisms remain unclear, I propose to identify molecular components that drive the effects of TRF on lipid metabolism. I will use Drosophila melanogaster, an advantageous model organism for this work because: many mammalian metabolic pathways are conserved in flies; flies have short generation time (2-3 months); and flies offer a plethora of powerful genetic tools. Aim 1 will identify specific tissue(s) in which circadian regulators are required for TRF-accelerated lipid usage. Aim 2 will examine the molecular mechanisms by which TRF changes lipid metabolism. I will use RNA-sequencing analysis to identify transcriptional differences between TRF-treated flies and their controls; significantly differentially expressed genes and/or pathways will be assessed for their functional role in TRF-accelerated lipid usage. Aim 3 will investigate the therapeutic potential of TRF in diet- induced obesity. Flies fed a high-sugar diet and have hallmarks of obesity will be treated with TRF to test if obesity-related phenotypes are ameliorated upon TRF treatment; we will test both young and old flies. These experiments will determine the molecular mechanisms connecting TRF to lipid metabolism and how TRF can be used to ameliorate obesity- and aging-related pathologies. This will improve our understanding on how TRF can confer health span benefits while also testing its therapeutic potential in aging-related, diet-induced obesity.