Metabolic Effects of Circadian-Based Dinner Time

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。证据是 越来越多的不适当的食物摄入时间导致了肥胖。吃得太晚与肥胖有关 和代谢综合征，表明昼夜节律失调可能是导致不良反应的机制 进食过晚的代谢后果。我们假设进食时间与内源性昼夜节律有关 决定新陈代谢结果的是节奏，而不是计时。在这项研究中，我们将使用暗光褪黑素 起搏(DLMO)是确定中枢昼夜节律输出的黄金标准，用于评估单个昼夜节律。 我们将使用DLMO来前瞻性地分配“早”(DLMO-3h)与“晚”(DLMO 1h)晚餐，同时保持 相同的睡眠时间(DLMO 2小时到10小时)，以评估是否可以可靠地诱导急性代谢功能障碍 或者通过在DLMO周围设定晚餐时间来防止。我们将使用每小时一次的血样来检测详细的血糖和 胰岛素谱、口服[2h31]棕榈酸酯示踪剂以量化饮食脂肪氧化，以及全室间接量热法 以测量总脂肪氧化。我们将招募体重正常的健康成年人(NWH)和肥胖成年人 和糖尿病前期(OPD)，因为后者人群特别容易患代谢性疾病，并可能衍生出 直接受益于我们的发现。具体目标是：1)量化基于DLMO的“早期”与 NWH和OPD成人餐后和过夜血糖和胰岛素水平的“晚”晚餐时间，2)测量 基于DLMO的“早”与“晚”晚餐时间对(A)外源/饮食和(B)总脂肪氧化的影响 NWH和OPD成人，以及3)检查昼夜节律标记物对预测迟发性疾病易感性的作用 进食导致的代谢功能障碍。对于目标1和目标2，我们将交叉随机选择16名NWH成人(8名男性，8名 女性)和16名门诊成人(8名男性，8名女性)到2次进餐时等卡路里进食的代谢 密室。对于目标3，我们将利用来自活动记录和摄取的经验证的昼夜节律指标 预测晚宴影响的温度传感器。 段医生的长期职业目标是成为一名独立的临床医生研究员，利用小说 对昼夜节律系统和新陈代谢之间的交集的机械洞察，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。她在寻找一个 K23导师职业发展奖，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。获奖期间的目标包括在 体内代谢研究的设计和实施以及在原则、实践和分析方法方面 睡眠和昼夜表型技术，通过结合有指导的研究经验，重点 课程，研究方法的实践学习，参加地方和国家会议，补助金 写作，领导力培训和经验。这项拟议的研究将为小说、昼夜节律-- 以进餐时间为基础，作为治疗肥胖和代谢障碍的精准医学方法。

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.