Effects of Time-restricted Eating versus Daily Continuous Calorie Restriction on Body Weight and Colorectal Cancer Risk Markers among Adults with Obesity

摘要。大约42%的美国成年人是肥胖的，数据表明， 肥胖者患结直肠癌的风险要高出30%。因此，有效的方法， 预防和治疗肥胖将对美国的CRC发病率产生重大影响。 通过生活方式干预限制是治疗肥胖症的最常见方法， 通过这种方法很难实现减肥，这是由于对卡路里监测的依从性低，这表明需要 for innovation革新.有时间限制的进食，一种间歇性禁食，已经在动物身上被证明是致癌的 保护作用，包括降低体重、减少全身炎症和改善血糖 新陈代谢.限时进食是指要求个人在一天内吃完一天的所有食物。 在规定的时间内，一天中剩下的几个小时里禁食。我们最近进行了两次短期的 （≤12周）限时进食的初步研究，以评价其安全性和对体重的初步疗效 和慢性疾病的风险标志物。我们的研究结果表明，干预是一种安全， 在肥胖的成年人中减肥是一种可接受的方法。此外，限制时间的饮食产生了 体重较基线减轻约3%，收缩压、氧化应激和 胰岛素抵抗尽管这些初步研究结果表明，有时间限制的饮食是一种有效的工具， 尽管肥胖个体的CRC风险降低，但这些数据仍然需要一个长期的有力证据来证实。 临床试验本建议旨在实施为期12个月（6个月的主动减肥阶段，6个月的 维持阶段），对照，平行臂试验，在255名肥胖成人（45-65岁）中进行， CRC风险。受试者将被随机分配至3组中的1组：1）限时进食（减肥阶段：每日ad 2）热量限制（体重减轻阶段：每日25%的热量限制），或 3)对照组（每日随意进食，无进餐时间限制）比较对以下方面的影响：（1）体重， 身体组成和干预依从性;（2）循环代谢、炎症和氧化应激- 相关生物标志物;（3）结肠粘膜基因表达谱和粘膜炎症，DNA损伤和 细胞生长;和（4）维持对体重/组成和全身/粘膜CRC风险的益处 标记。这项建议将由一个具有营养科学专门知识的跨学科小组领导， 饮食、行为科学、癌症分子标记、胃肠病学和生物统计学。如果这件事的目的 建议实现，它将首次表明，时间限制饮食可以作为一种新颖的实施， 传统节食的替代方案（即，每日热量限制）用于控制体重和降低成人CRC风险 肥胖症这项拟议的研究也将是第一次也是最全面的分子检查， 调节时间限制饮食和热量限制的抗癌作用的机制。

ABSTRACT. Approximately 42% of the U.S. adult population is obese and data suggests that persons with obesity are at a 30% greater risk of developing colorectal cancer (CRC). Therefore, efficacious approaches to preventing and treating obesity will have significant effects on CRC incidence in the U.S. Although calorie restriction through lifestyle intervention is the most common approach to treat obesity, clinically meaningful weight loss is difficult to achieve via this method due to low adherence with calorie monitoring, indicating a need for innovation. Time-restricted eating, a type of intermittent fasting, has been shown in animals to impart cancer protective effects including lower body weight, decreased systemic inflammation, and improved glucose metabolism. Time-restricted eating is where individuals are asked to consume all their food for the day within a specified time frame, and water fast for the remaining hours of the day. We recently performed two short-term (≤12-weeks) pilot studies of time-restricted eating to evaluate its safety and preliminary efficacy on body weight and chronic disease risk markers in adults with obesity. Our results show the intervention is a safe and acceptable approach to weight loss among obese adults. Moreover, time-restricted eating produced approximately 3% weight loss from baseline and reductions in systolic blood pressure, oxidative stress and insulin resistance. Although these pilot findings show promise for time-restricted eating as an effective tool for CRC risk reduction among obese individuals, these data still require confirmation by a well powered longer-term clinical trial. The present proposal aims to implement a 12-month (6-month active weight loss phase, 6-month maintenance phase), controlled, parallel arm trial among 255 obese adults (45-65 years old) who are at elevated CRC risk. Subjects will be randomized to 1 of 3 groups: 1) Time-restricted eating (weight loss phase: daily ad libitum food intake from 11am – 7pm), 2) Calorie restriction (weight loss phase: daily 25% calorie restriction), or 3) Control (daily ad libitum food intake, no meal timing restrictions) to compare the effects on: (1) Body weight, body composition, and intervention adherence; (2) Circulating metabolic, inflammation, and oxidative stress- related biomarkers; (3) Colonic mucosal gene expression profiles and mucosal inflammation, DNA damage and cellular growth; and (4) maintenance of benefits on body weight/composition and systemic/mucosal CRC risk markers. This proposal will be led by a transdisciplinary team with expertise in nutrition science, time-restricted eating, behavioral science, molecular markers of cancer, gastroenterology, and biostatistics. If the aims of this proposal are achieved, it will show for the first time that time-restricted eating can be implemented as a novel alternative to traditional dieting (i.e., daily calorie restriction) for weight control and CRC risk reduction in adults with obesity. The proposed study will also be the first and most comprehensive examination of molecular mechanisms that mediate the anticancer effects of time-restricted eating and calorie restriction.