Diurnal rhythm in nutrient metabolism for metabolic homeostasis

营养代谢的昼夜节律促进代谢稳态

• 批准号: 9923646
• 负责人: Satchidananda Panda
• 金额: $ 67.34万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-10 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923646
• 关键词: ARNTL gene; Animal Model; Animals; Attenuated; Behavioral; Body Weight; Cardiovascular Diseases; Chronic; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Combined Modality Therapy; Complex; Consumption; Diabetes Mellitus; Diet; Disease; Diurnal Rhythm; Eating; Endocrine; Environment; Environmental Impact; Etiology; Exhibits; Fasting; Foundations; Future; Gene Expression; General Population; Genes; Genetic; Genetic Models; Genotype; Health; Hepatic; High Fat Diet; Homeostasis; Hour; House mice; Human; Hyperlipidemia; Incidence; Insecta; Insulin Resistance; Intervention; Jet Lag Syndrome; Knock-out; Light; Link; Liver; Measures; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Nature; Nutrient; Obesity; Organ; Pathway interactions; Pattern; Phase; Physiology; Plant Roots; Populations at Risk; Prevention; Prevention therapy; Regulation; Role; Schedule; Sleep; System; Testing; Therapeutic; Time; Time-restricted feeding; Transcript; Translations; Wakefulness; Weight Gain; Wild Type Mouse; Work; attenuation; blood glucose regulation; cardiometabolism; circadian; circadian pacemaker; circadian regulation; cohort; combat; epidemiology study; experimental study; feeding; gene function; human model; improved; metabolic phenotype; nonalcoholic steatohepatitis; novel; nutrient metabolism; nutrition; obesity risk; prevent; protein metabolite; public health relevance; shift work; time interval; transcriptome

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.

抽象的 代谢稳态的破坏越来越被认为是肥胖，胰岛素抵抗的根本原因， 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 疗法的重点是介导营养利用率，互转换和存储的关键组件。 但是，代谢性疾病本质上是复杂的，在多种途径中破坏了，通常需要 逐渐复杂的组合疗法。新颖的干预措施是有效的预防性 迫切需要方法和增强治疗。昼夜节律对代谢和生理的调节 为预防和治疗这些疾病提供新颖的有希望的途径。有增长 在做班劳动中发生的睡眠和营养中自然昼夜节律中断的证据是 与人类代谢疾病的发生率增加有关。此外，即使是一般 人口，睡眠和营养的每日节奏受到严重破坏。因此，行为改变了 维持强大的昼夜节律功能被认为是有益于易受挑战的挑战 代谢疾病。时间限制的喂养（TRF），其中动物在8-12小时的时间间隔内喂养 在他们自然的昼夜节律中，清醒的时间既是预防性的，也是针对代谢疾病的治疗性 小鼠和昆虫。越来越优先的食物摄入时间对 人体体重调节。尽管这些初步发现令人鼓舞，但仍有主要问题 在任何潜在的人类翻译之前得到回答。在轮班范式下，TRF是有益的 长期破坏昼夜节律？ TRF益处的潜在机制是什么？这 建议将在小鼠中测试这些问题，这些问题有效地用于建模昼夜节律的破坏和 代谢疾病。