Development of countermeasures against adverse metabolic effects of shift work

描述（由申请人提供）：倒班工作会增加患糖尿病、肥胖和心血管疾病的风险，这不能完全用生活方式和社会经济地位的差异来解释。最近，我们证明了昼夜节律失调，即中央昼夜节律起搏器与行为睡眠/觉醒周期之间的失调（这在倒班工人中很典型），在保持热量摄入和身体活动不变的情况下，会导致不利的代谢变化。这些发现可能有助于解释轮班工作对健康的不良影响。最近，我们还在一项前瞻性研究中证明，吃饭的时间可以预测减肥治疗的成功，而不依赖于热量摄入、活动和睡眠时间。进餐时间的重要性与动物实验工作是一致的，实验表明，使禁食/摄食周期的昼夜节律时间正常化（不使睡眠/觉醒周期正常化）可以防止这种不利的代谢影响。此外，中央起搏器和禁食/摄食周期之间的不同步导致身体其他部位的中央昼夜节律起搏器和周围昼夜节律振荡器之间的不同步，特别是在肝脏和胰腺等代谢器官中，这种现象被称为“内部不同步”，这可能与昼夜节律失调的不良代谢后果有关。然而，到目前为止，还没有证据支持或反对人类内部不同步的发展，可能是因为测试这一假设所需的苛刻和复杂的昼夜节律协议。在目前的提案中，我们将测试操纵食物摄入的时间是否可以防止昼夜节律失调的不良代谢影响（目的1），以及中央昼夜节律起搏器和行为周期之间的不同步是否会导致人类内部不同步（目的2）。由于轮班工作的劳动力比例很高，后果严重，因此该建议具有重要的临床意义，并为以后开发新的治疗方法奠定了科学基础，以对抗慢性暴露的弱势人群中增加的心脏代谢疾病风险。

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.