Metabolic Effects of Circadian-Based Dinner Time

基于昼夜节律的晚餐时间的代谢影响

• 批准号: 10506606
• 负责人: Daisy Duan
• 金额: $ 20.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506606
• 关键词: Acute; Adult; Award; Blood specimen; Circadian Rhythms; Circadian desynchrony; Dietary Fats; Eating; Enrollment; Fatty acid glycerol esters; Food; Foundations; Funding; Glucose; Goals; Gold; Grant; Hour; Human; Indirect Calorimetry; Individual; Insulin; Intervention; K-Series Research Career Programs; Late Effects; Lead; Leadership; Light; Measures; Melatonin; Mentors; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Methods; Morbidity - disease rate; Obesity; Oral; Outcome; Output; Palmitates; Phase; Phenotype; Population; Prediabetes syndrome; Predisposition; Prevention; Randomized; Research; Research Methodology; Research Personnel; Sleep; System; Techniques; Time; Tracer; Training; Woman; Writing; actigraphy; adult obesity; analytical method; base; career; circadian; design; dietary; experience; feeding; hands-on learning; healthy weight; in vivo; insight; men; metabolic abnormality assessment; mortality; novel; obesity treatment; oxidation; precision medicine; prevent; programs; prospective; skills; symposium

Obesity and its metabolic complications are leading causes of morbidity and mortality in the world. Evidence is mounting that inappropriate timing of food intake contributes to obesity. Late eating is associated with obesity and metabolic syndrome, suggesting that circadian misalignment may be the mechanism underlying the adverse metabolic consequences of late eating. We hypothesize that meal timing in relation to the endogenous circadian rhythm, rather than to clock hour, determines metabolic outcomes. In this study, we will use dim light melatonin onset (DLMO), the gold-standard for ascertaining central circadian output, to assess individual circadian rhythms. We will use DLMO to prospectively assign “early” (DLMO-3h) vs “late” (DLMO+1h) dinner while maintaining the same sleep times (DLMO+2h to +10h) to evaluate whether acute metabolic dysfunction can be reliably induced or prevented by setting dinner times around DLMO. We will use hourly blood sampling for detailed glucose and insulin profiles, oral [2H31] palmitate tracer to quantify dietary fat oxidation, and whole-room indirect calorimetry to measure total fat oxidation. We will enroll both normal-weight healthy adults (NWH) and adults with obesity and prediabetes (OPD), as the latter population is particularly vulnerable to metabolic diseases and could derive immediate benefit from our findings. The specific aims are to: 1) Quantify the impact of DLMO-based “early” vs. “late” dinner time on post-prandial and overnight glucose and insulin levels in NWH and OPD adults, 2) Measure the impact of DLMO-based “early” vs. “late” dinner time on (a) exogenous/dietary and (b) total fat oxidation in NWH and OPD adults, and 3) Examine the utility of circadian phase markers to predict susceptibility to late eating-induced metabolic dysfunction. For Aims 1 and 2, we will crossover-randomize 16 NWH adults (8 men, 8 women) and 16 OPD adults (8 men, 8 women) to the 2 dinner times with isocaloric feeding in a metabolic chamber. For Aim 3, we will leverage validated circadian metrics derived from actigraphy and ingestible thermosensors to predict effects of late dinner. Dr. Daisy Duan’s long-term career goal is to become an independent clinician investigator leveraging novel mechanistic insights that underly the intersection between the circadian system and metabolism to design and validate interventions for the prevention and treatment of obesity and its metabolic complications. She seeks a K23 mentored career development award to gain critical skills and experience in order to effectively lead an independently-funded research program. The goals during the award period include developing expertise in the design and implementation of in vivo metabolic studies and in the principles, practice, and analytical methods in sleep and circadian phenotyping techniques, through a combination of mentored research experience, focused coursework, hands-on learning in research methodology, participation in local and national conferences, grant writing, and leadership training and experience. The proposed study will lay the foundation for novel, circadian- based meal timing as a precision medicine approach to obesity and metabolic dysfunction.

肥胖及其代谢并发症是世界上发病率和死亡率的主要原因。证据 不适当的食物摄入时间会导致肥胖。晚吃饭与肥胖有关 和代谢综合征，这表明昼夜节律失调可能是不利的潜在机制， 晚吃的代谢后果。我们假设进餐时间与内源性昼夜节律有关， 节奏，而不是时钟小时，决定代谢结果。在本研究中，我们将使用暗光褪黑激素 发病（DLMO），确定中央昼夜输出的金标准，以评估个人的昼夜节律。 我们将使用DLMO前瞻性地分配“早”（DLMO-3小时）与“晚”（DLMO+1小时）晚餐，同时保持 相同的睡眠时间（DLMO+2 h至+10 h），以评估是否可以可靠地诱导急性代谢功能障碍 或通过将晚餐时间设定在DLMO附近来防止。我们将每小时采集一次血液样本，以获得详细的葡萄糖， 胰岛素谱、定量膳食脂肪氧化口服[2 H31]棕榈酸示踪剂和全室间接量热法 来测量脂肪氧化总量我们将招募正常体重的健康成人（NWH）和肥胖成人 和糖尿病前期（OPD），因为后者特别容易患代谢性疾病， 立即受益于我们的发现。具体目标是：1）量化基于DLMO的“早期”与 “晚”晚餐时间对NWH和OPD成人餐后和过夜血糖和胰岛素水平的影响，2）测量 基于DLMO的“早”与“晚”晚餐时间对（a）外源性/饮食和（B）总脂肪氧化的影响， NWH和OPD成人，以及3）检查昼夜节律相位标记物预测晚期乳腺癌易感性的效用。 进食引起的代谢紊乱对于目标1和2，我们将交叉随机化16名NWH成人（8名男性，8名 女性）和16名OPD成年人（8名男性，8名女性）在代谢中进行2次晚餐等热量喂养 室。对于目标3，我们将利用从体动记录仪和可摄入量中获得的经验证的昼夜节律指标， 温度传感器来预测晚餐过晚的影响。 博士Daisy Duan的长期职业目标是成为一名独立的临床研究者， 机械的见解，基础之间的交叉昼夜节律系统和代谢，以设计和 验证预防和治疗肥胖及其代谢并发症的干预措施。她寻求一个 K23辅导职业发展奖，以获得关键技能和经验，以有效地领导 独立资助的研究项目。奖励期间的目标包括发展以下方面的专门知识： 体内代谢研究的设计和实施，以及原理、实践和分析方法， 睡眠和昼夜节律表型技术，通过结合指导的研究经验， 课程作业、研究方法的实践学习、参加地方和国家会议、赠款 写作、领导力培训和经验。这项研究将为新的昼夜节律奠定基础- 基于进餐时间的精确医学方法来治疗肥胖和代谢功能障碍。