Diurnal rhythm in nutrient metabolism for metabolic homeostasis

摘要 代谢平衡失调日益被认为是肥胖、胰岛素抵抗、 非酒精性脂肪性肝炎、高脂血症和心血管疾病。目前在预防和预防方面的努力 治疗的重点是调节养分利用、相互转化和储存的关键成分。 然而，代谢性疾病本质上是复杂的，具有多个途径的中断，通常需要 逐渐变得更加复杂的联合疗法。既是有效的预防措施，又是有效的新型干预措施 方法和加强治疗是当务之急。代谢和生理的昼夜节律 为预防和治疗这些疾病提供了一条新的有希望的途径。有越来越多的 有证据表明，睡眠和营养的自然昼夜节律被打乱，就像人们倒班时发生的那样 与人类代谢性疾病发病率增加有关。此外，即使在普通民众中， 人口中，睡眠和营养的日常节律被严重打乱。因此，行为的改变 维持强健的昼夜节律功能被认为有益于应对容易患上 代谢性疾病。限时喂食(TRF)，在8-12小时的时间间隔内喂食动物 在自然的昼夜节律中，保持清醒既可以预防也可以治疗人体内的代谢性疾病 无论是老鼠还是昆虫。越来越多的先例表明，食物摄入的时间对 人体的体重调节。虽然这些初步调查结果令人鼓舞，但主要问题仍然存在。 在任何潜在的人工翻译之前都要得到回答。在轮班工作模式下，TRF是否有益 慢性地扰乱昼夜节律？扶轮基金会受益的潜在机制是什么？这 该提案将在小鼠身上测试这些问题，这些小鼠被有效地用来模拟昼夜节律紊乱和 代谢性疾病。

Abstract Disruption in metabolic homeostasis is increasingly recognized as the root cause of obesity, insulin resistance, nonalcoholic steatohepatitis, hyperlipidemia, and cardiovascular diseases. Current efforts on prevention and therapies are focused on key components that mediate nutrient utilization, interconversion and storage. However, metabolic diseases are complex in nature with disruption in multiple pathways, often requiring progressively more complex combination therapies. Novel intervention that is effective both as a preventative method and to augment therapy is urgently needed. The circadian regulation of metabolism and physiology offer a novel promising avenue for the prevention and the treatment of these diseases. There is growing evidence that disruption of natural circadian rhythm in sleep and nutrition as occurs in people doing shiftwork is associated with increased incidence of metabolic diseases in humans. Furthermore, even among the general population, the daily rhythm of sleep and nutrition is significantly disrupted. Therefore, behavioral changes that sustain robust circadian function are considered to be beneficial against challenges that predispose to metabolic diseases. Time-restricted feeding (TRF), in which animals are fed within an 8-12 hour time interval during their natural circadian wakeful hours is both preventative and therapeutic against metabolic diseases in both mice and insects. There is growing precedence that the time of food intake has a profound impact on body weight regulation in humans. While these preliminary findings are encouraging, major questions remain to be answered before any potential human translation. Is TRF beneficial under a shiftwork paradigm that chronically disrupts circadian rhythm? And what are the potential mechanisms underlying TRF benefits? This proposal will test these questions in mice that are effectively used to model circadian rhythm disruption and metabolic diseases.