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.

项目概要今天，我们生活在一个前所未有地获得食物的时代。最近的研究表明，许多美国人吃从他们醒来到入睡。具体来说，夜间饮食与多种衰老有关—— 相关合并症，包括肥胖、心血管疾病和 2 型糖尿病。虽然很多事情正在进行中研究调查了饮食成分影响新陈代谢的机制，但人们对如何影响新陈代谢的了解还较少喂食时间影响新陈代谢。为此，改变喂养时间的饮食干预已事实证明，即使不减少热量摄入，也能保护健康的许多方面。限时喂食 (TRF) 饮食已在小鼠和人类中被证明可以减少氧化应激和炎症，降低胰岛素水平抵抗力、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，并预防肥胖。 Shirasu-Hiza 实验室利用黑腹果蝇开发了一种强大的 TRF 饮食，延长寿命并延缓衰老的分子迹象，例如蛋白质聚集，并表明 TRF 增强昼夜节律基因表达，并需要生物钟来赋予寿命益处。此外，我们发现 TRF 似乎可以重新编程脂质代谢； TRF 处理后，果蝇通过利用脂质的增加速度比对照组快得多，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，这是这项工作的一种有利的模式生物，因为：哺乳动物的代谢途径在果蝇中是保守的；苍蝇世代时间短（2-3个月）；和苍蝇提供了大量强大的遗传工具。目标 1 将确定昼夜节律调节因子所在的特定组织 TRF 加速脂质使用所需。目标 2 将检查 TRF 变化的分子机制脂质代谢。我将使用 RNA 测序分析来识别 TRF 处理之间的转录差异苍蝇及其控制措施；将评估显着差异表达的基因和/或途径 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发肥胖。喂食高糖饮食并具有肥胖特征的苍蝇将接受 TRF 治疗，以测试是否 TRF 治疗后肥胖相关表型得到改善；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 如何发挥作用用于改善肥胖和衰老相关的病症。这将加深我们对 TRF 如何发挥作用的理解赋予健康跨度益处，同时还测试其在与衰老相关的饮食引起的肥胖方面的治疗潜力。