Development of countermeasures against adverse metabolic effects of shift work

说明(申请人提供)：倒班工作会增加患糖尿病、肥胖症和心血管疾病的风险，这不能用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失调，即中央昼夜节律起搏器和行为睡眠/清醒周期之间的失调(这在倒班工人中是典型的)，同时保持热量摄入和体力活动不变，会导致不利的代谢变化。这些发现可能有助于解释倒班工作对健康的不利影响。最近，我们还在一项前瞻性研究中证明，进餐时间预测减肥治疗的成功，与卡路里摄入量、活动和睡眠时间无关。进食时间的重要性与动物实验工作一致，表明正常化禁食/喂食周期的昼夜节律(而不是正常化睡眠/醒来周期)可以防止这种不利的代谢影响。此外，中央起搏器和禁食/进食周期之间的不同步会导致身体其他部位，特别是肝脏和胰腺等代谢器官的中央昼夜节律起搏器和外周昼夜节律振荡器之间的不同步，这一现象被称为“内部不同步”，这可能与昼夜节律不对齐的不利代谢后果有关。然而，到目前为止，还没有证据支持或反对人类内部去同步化的发展，这可能是因为测试这一假设所需的苛刻和复杂的昼夜节律。在目前的提案中，我们将测试控制食物摄入的时间是否可以防止昼夜节律失调的不利代谢影响(目标1)，以及中央昼夜节律起搏器和行为周期之间的去同步是否会导致人类内部的去同步(目标2)。由于高比例的劳动力暴露于倒班工作和严重的后果，这一建议具有很大的临床意义，并为以后开发一种新的治疗方法奠定了科学基础，以对抗在这一长期暴露的脆弱人群中心脏代谢紊乱风险的增加。

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.