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

基本信息

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
项目类别：
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

项目摘要

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，我们生活在空前获得食物的时代。最近的研究表明，许多美国人吃从他们醒来到入睡的时间。特别是夜间吃与几个老化有关的相关的合并症，包括肥胖，心血管疾病和2型糖尿病。虽然正在进行很多研究调查了饮食成分影响新陈代谢的机制，尚不清楚如何喂养的时机会影响新陈代谢。为此，改变喂养时间的饮食干预措施有被证明可以保护健康的许多方面，即使没有减少热量摄入量。时间限制的喂养（TRF）在小鼠和人类中已经显示了饮食以减少氧化应激和炎症，减少胰岛素抗性，较低的血糖。在小鼠中，TRF已显示可降低脂肪水平，防止高脂饮食，并防止肥胖。 Shirasu-Hiza Lab使用果蝇Melanogaster开发了一种强大的TRF饮食延长寿命并延迟衰老的分子体征，例如蛋白质聚集，并表明TRF 增强昼夜节律的表达，并需要昼夜节律赋予寿命益处。另外，我们发现TRF似乎重新编程了脂质代谢。 TRF治疗后，苍蝇通过利用而响应禁食脂质比对照更快，导致三酰基甘油三酸酯损失和饥饿敏感性增加。我发现这种TRF加速的脂质使用（例如TRF诱导的寿命延长）需要昼夜节律组件但是，与TRF诱导的寿命扩展不同，不需要自噬组件。因为基础机制尚不清楚，我建议确定驱动TRF对脂质影响的分子成分代谢。我将使用果蝇Melanogaster，这是这项工作的有利模型有机体，因为：许多哺乳动物的代谢途径在苍蝇中保守；苍蝇的生成时间很短（2-3个月）；和苍蝇提供大量强大的遗传工具。 AIM 1将识别昼夜节律调节器的特定组织 trf加速脂质的使用所需。 AIM 2将检查TRF改变的分子机制脂质代谢。我将使用RNA序列分析来识别TRF处理的转录差异苍蝇及其控制；将评估明显差异表达的基因和/或途径在TRF加速脂质使用中的功能作用。 AIM 3将研究TRF在饮食中的治疗潜力 - 诱发肥胖。喂养高糖饮食的苍蝇，并具有肥胖标志，将用TRF治疗，以测试是否存在 TRF治疗后，与肥胖相关的表型得到改善；我们将测试年轻的和老苍蝇。这些实验将确定将TRF连接到脂质代谢的分子机制以及如何成为TRF 用于改善肥胖症和衰老相关的病理。这将提高我们对TRF的理解赋予健康跨度的益处，同时还测试其在与衰老相关的，饮食引起的肥胖症中的治疗潜力。