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

限时喂养对脂质代谢影响的机制

• 批准号: 10537006
• 负责人: Jared Anthony Gatto
• 金额: $ 4.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537006
• 关键词: Acceleration; Affect; Age; Aging; American; Animal Model; Animals; Automobile Driving; Autophagocytosis; Blood Glucose; Body Weight decreased; Brain; Candidate Disease Gene; Cardiovascular Diseases; Catabolism; Circadian gene expression; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Diet; Dietary Component; Dietary Intervention; Drosophila genus; Drosophila melanogaster; Eating; Energy Intake; Fasting; Fat Body; Fatty acid glycerol esters; Food; Gene Expression; Generations; Genes; Genetic; Goals; Health; Health Benefit; High Fat Diet; Hour; Human; Inflammation; Insulin Resistance; Intestines; Life; Light; Link; Lipids; Longevity; Mammals; Mediating; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Organism; Oxidative Stress; Pathology; Pathway interactions; Peripheral; Persons; Phenotype; Physiological; Research; Resistance; Role; Sleep; Starvation; Testing; Therapeutic; Thin Layer Chromatography; Time; Time-restricted feeding; TimeLine; Tissues; Work; age effect; anti aging; circadian; circadian pacemaker; circadian regulation; comorbidity; diet-induced obesity; differential expression; experimental study; feeding; fly; healthspan; human old age (65+); improved; interest; knock-down; lipid metabolism; mutant; obesity prevention; obesity risk; prevent; protein aggregation; sugar; tool; transcriptome sequencing

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.

项目摘要 今天，我们生活在一个前所未有的获取食物的时代。最近的研究表明，许多美国人吃 从他们醒来到他们入睡。尤其是晚上吃东西，与几种衰老有关- 相关合并症，包括肥胖、心血管疾病和2型糖尿病。虽然许多工作正在进行， 研究调查了饮食成分影响新陈代谢的机制，但对如何影响新陈代谢的了解较少。 进食的时间会影响新陈代谢。为此，改变喂养时间的饮食干预措施， 已被证明可以保护健康的许多方面，即使不减少热量摄入。限时进食 (TRF)在小鼠和人类中，饮食可以减少氧化应激和炎症， 抵抗力，降低血糖。在小鼠中，TRF已被证明可以降低脂肪水平，防止高脂肪饮食， 预防肥胖。Shirasu-Hiza实验室利用黑腹果蝇开发了一种强大的TRF饮食， 延长寿命，延缓衰老的分子迹象，如蛋白质聚集，并表明TRF 增强昼夜节律基因表达并需要昼夜节律钟来赋予寿命益处。另外我们 发现TRF似乎重新编程脂质代谢; TRF治疗后，苍蝇通过利用 脂质比对照快得多，导致三酰甘油损失率和饥饿敏感性增加。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 但与TRF诱导的寿命延长不同，它不需要自噬成分。因为底层 机制仍不清楚，我建议确定分子组成部分，驱动TRF对脂质的影响 新陈代谢.我将使用果蝇，一个有利的模式生物这项工作，因为：许多 哺乳动物的代谢途径在果蝇中是保守的;果蝇的世代时间短（2-3个月）; 提供了大量强大的遗传工具。目的1将确定特定的组织（S），其中昼夜节律调节器是 需要TRF加速脂质使用。目标2将研究TRF变化的分子机制 脂质代谢我将使用RNA测序分析，以确定TRF治疗之间的转录差异， 果蝇及其对照;将评估显著差异表达的基因和/或途径， 在TRF加速脂质使用中的功能作用。目的3将研究TRF在饮食中的治疗潜力- 诱发性肥胖喂食高糖饮食并具有肥胖特征的苍蝇将接受TRF治疗，以测试 肥胖相关的表型在TRF治疗后得到改善;我们将测试年轻和年老的果蝇。这些 实验将确定TRF与脂质代谢之间的分子机制，以及TRF如何被 用于改善肥胖和衰老相关的病理。这将增进我们对扶轮基金会如何能 赋予健康寿命的好处，同时也测试其在衰老相关的饮食诱导的肥胖症中的治疗潜力。