Development of countermeasures against adverse metabolic effects of shift work

针对轮班工作对代谢的不良影响制定对策

• 批准号: 9245725
• 负责人: FRANK A SCHEER
• 金额: $ 64.83万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245725
• 关键词: Address; Animals; Automobile Driving; Behavioral; Biological; Body Weight decreased; Cardiovascular Diseases; Chronic; Circadian Rhythms; Circadian desynchrony; Complex; Development; Diabetes Mellitus; Diet; Disease; Dissociation; Eating; Energy Intake; Exposure to; Fasting; Foundations; Glucose; Health; Human; Lead; Leptin; Life Style; Light; Liver; Melatonin; Metabolic; Metabolic Marker; Obesity; Organ; Pacemakers; Pancreas; Participant; Peripheral; Phase; Physical activity; Prospective Studies; Protocols documentation; Publishing; Research; Rest; Risk; Rodent; Role; Schedule; Sleep; Sleep Wake Cycle; Slow-Wave Sleep; Socioeconomic Status; Testing; Training; Tweens; Vulnerable Populations; Work; cardiometabolic risk; circadian pacemaker; clinically relevant; design; diabetes risk; feeding; feeding schedule; insight; novel therapeutic intervention; obesity risk; prevent; public health relevance; shift work; success; Address; Animals; Automobile Driving; Behavioral; Biological; Body Weight decreased; Cardiovascular Diseases; Chronic; Circadian Rhythms; Circadian desynchrony; Complex; Development; Diabetes Mellitus; Diet; Disease; Dissociation; Eating; Energy Intake; Exposure to; Fasting; Foundations; Glucose; Health; Human; Lead; Leptin; Life Style; Light; Liver; Melatonin; Metabolic; Metabolic Marker; Obesity; Organ; Pacemakers; Pancreas; Participant; Peripheral; Phase; Physical activity; Prospective Studies; Protocols documentation; Publishing; Research; Rest; Risk; Rodent; Role; Schedule; Sleep; Sleep Wake Cycle; Slow-Wave Sleep; Socioeconomic Status; Testing; Training; Tweens; Vulnerable Populations; Work; cardiometabolic risk; circadian pacemaker; clinically relevant; design; diabetes risk; feeding; feeding schedule; insight; novel therapeutic intervention; obesity risk; prevent; public health relevance; shift work; success

DESCRIPTION (provided by applicant): Shift work is associated with an increased risk for the development of diabetes, obesity, and cardiovascular disease, which cannot be fully explained by differences in life style and socioeconomic status. Recently, we demonstrated that circadian misalignment, the misalignment between the central circadian pacemaker and the behavioral sleep/wake cycle (that is typical in shift workers), while keeping caloric intake and physical activity constant, leads to adverse metabolic changes. These findings may help explain the adverse health consequences of shift work. More recently, we also demonstrated in a prospective study that the timing of meals predicts the success of weight loss therapy, independent of caloric intake, activity and sleep duration. The importance of meal timing is consistent with animal experimental work showing that normalizing the circadian timing of the fasting/feeding cycle (without normalizing the sleep/wake cycle) prevents such adverse metabolic effects. Furthermore, misalignment between the central pacemaker and the fasting/feeding cycle leads to desynchrony between the central circadian pacemaker and peripheral circadian oscillators in the rest of the body, especially in metabolic organs such as liver and pancreas, a phenomenon known as "internal desynchrony", which may relate to the adverse metabolic consequences of circadian misalignment. However, to date there exists no evidence for or against the development of internal desynchrony in humans, likely because of the demanding and complex circadian protocols required to test that hypothesis. In the current proposal, we will test whether manipulating the timing of food intake prevents the adverse metabolic effects of circadian misalignment (Aim 1), and whether desynchrony between the central circadian pacemaker and the behavioral cycle leads to internal desynchrony in humans (Aim 2). Because of the high proportion of the work force exposed to shift work and the grave consequences, this proposal has great clinical relevance and lays the scientific foundation for later development of a novel therapeutic approach against the increased risk for cardiometabolic disorders in this vulnerable population with chronic exposure.

描述（由申请人提供）：轮班工作与增加糖尿病，肥胖和心血管疾病的风险增加有关，这无法完全通过生活方式和社会经济地位的差异来完全解释。最近，我们证明了昼夜节律的未对准，中央昼夜节奏起搏器与行为睡眠/唤醒周期之间的错位（在移位工人中是典型的），同时保持热量的摄入量和体育活动持续，从而导致不良代谢变化。这些发现可能有助于解释轮班工作的不利健康后果。最近，我们还在一项前瞻性研究中证明，餐食的时间可以预测减肥疗法的成功，与热量摄入，活动和睡眠持续时间无关。进餐时间的重要性与动物实验工作一致，表明将禁食/喂养周期的昼夜节律正常化（不使睡眠/唤醒周期归一化）阻止了这种不良代谢作用。此外，中央起搏器与禁食/喂养周期之间的错位导致身体其他身体中中部昼夜节律起搏器与外围昼夜节律振荡者之间的异步，尤其是在肝脏和胰腺等代谢性质上，诸如肝脏和胰腺等代谢，这是一种crip的现象。但是，迄今为止，还没有证据表明或反对人类内部降解的发展，这很可能是由于检验该假设所需的苛刻且复杂的昼夜节律。在当前的提案中，我们将测试操纵食物摄入的时机是否可以防止昼夜节律未对准的不良代谢作用（AIM 1），以及中央昼夜节律起搏器与行为周期之间的脱节是否会导致人类内部脱离人类（AIM 2）。由于暴露于转移工作和严重后果的劳动力比例很高，因此该提案具有很大的临床意义，并为后来发展一种新型治疗方法的科学基础，以与这一较脆弱人群中慢性暴露的心脏代谢风险增加的风险增加。