Development of countermeasures against adverse metabolic effects of shift work

描述（由申请人提供）：轮班工作与糖尿病，肥胖和心血管疾病的发展风险增加有关，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，中央昼夜节律起搏器和行为睡眠/觉醒周期（这在轮班工人中很典型）之间的失调，同时保持热量摄入和体力活动恒定，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，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一致，动物实验工作表明，使禁食/进食周期的昼夜节律时间正常化（而不使睡眠/觉醒周期正常化）可以防止这种不良代谢作用。此外，中枢起搏器与禁食/进食周期之间的不对准导致身体其余部分中的中枢昼夜节律起搏器与外周昼夜节律振荡器之间的失调，特别是在诸如肝脏和胰腺的代谢器官中，这是一种被称为“内部失调”的现象，其可能与昼夜节律不对准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发育的发展，可能是因为测试这一假设所需的要求和复杂的昼夜节律协议。在目前的提案中，我们将测试是否操纵食物摄入的时间可以防止昼夜节律失调的不良代谢影响（目标1），以及中央昼夜节律起搏器和行为周期之间的失调是否会导致人类的内部失调（目标2）。由于暴露于轮班工作的劳动力比例很高，后果严重，因此该提案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，以防止这种慢性暴露的脆弱人群中心脏代谢疾病的风险增加。

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.