Circadian disruption and bariatric surgery: impact on metabolism, clock biology

描述（由申请人提供）：大约7800万美国成年人被归类为肥胖，体重指数大于30 kg/m2。严重的心脏代谢健康威胁，如糖尿病、心脏病、中风和癌症都与肥胖有关。有趣的是，在正常昼夜节律被破坏的人群中也观察到体重增加过多和代谢紊乱风险增加（例如，夜班工人和夜间进食综合征患者）。目前，最成功的治疗严重肥胖和糖尿病是减肥手术。虽然众所周知，减肥手术的成功程度因人而异，但差异的确切原因 是未知的。鉴于约40%的减肥手术人群也有一定程度的昼夜节律紊乱（CD），昼夜节律紊乱可能会影响减肥手术的结果。研究昼夜节律在代谢的正常和失调方面发挥的重要作用标志着一种新的综合方法，以更好地了解肥胖和糖尿病。拟议的实验将通过研究环境或遗传CD的有害代谢后果是否可以通过减肥手术逆转来阐明关键的昼夜节律和代谢联系。具体而言，该提案利用我们的实验室开发的啮齿动物模型的日益流行的减肥手术程序称为垂直袖状胃切除术。使用该模型，我们将1）研究环境和遗传CD如何影响减肥手术的结果，2）减肥手术是否以及如何改善肥胖诱导的昼夜节律生物学变化。通过使用重复的光变化来反映人类的“夜班工作”和时间限制的喂养来反映患有“夜食综合征”的患者，该提议在允许机械研究的背景下有效地模拟了人类CD。此外，通过利用具有昼夜节律和代谢障碍的Clock突变小鼠，该提议还研究了遗传对减肥手术成功的影响。本提案的目标可以通过一个独特的研究培训计划来实现，该计划将研究者在昼夜节律方面的专业知识与内分泌学、代谢和体重调节方面的新技术、概念和程序相结合。这些拟议实验的成功执行将产生两个重要影响。首先，它将揭示临床相关信息，以确定CD患者对减肥手术的反应是否较低。其次，通过将昼夜节律生物学的分子和行为方面与减肥手术对多种代谢系统的强大影响相结合，它将为将昼夜节律与代谢疾病联系起来的关键机制提供相当多的信息。这将提供对代谢性疾病的病因学的深入了解，因为它们与昼夜节律生物学有关，并且还提供潜在的治疗策略，这些治疗策略可以通过侵入性更小和更定制的手段来模拟减肥手术的关键分子和生理作用。

DESCRIPTION (provided by applicant): About 78 million American adults are classified as obese, with a body mass index greater than 30 kg/m2. Serious cardiometabolic health threats such as diabetes, heart disease, stroke, and cancer have been linked to obesity. Interestingly, excess weight gain and an increased risk for metabolic disorders are also observed within populations subjected to a disruption of their normal circadian rhythm (e.g., night-shift workers and patients with Night Eating Syndrome). Currently, the most successful treatment for severe obesity and diabetes is bariatric surgery. While it is known that the degree of success of bariatric surgery varies greatly from one individual to another, the exact reasons for the variance are unknown. Given that ~40% of the bariatric surgery population also have some degree of circadian disruption (CD), it is possible that disrupted circadian biology can influence the outcome of bariatric surgery. Investigating the important role that circadian rhythms play in normal and dysregulated aspects of metabolism marks a novel, integrative approach to better understanding obesity and diabetes. The proposed experiments will elucidate key circadian and metabolic connections by studying whether the deleterious metabolic consequences of environmental or genetic CD can be reversed by bariatric surgery. Specifically, this proposal utilizes our laboratory-developed rodent model of the increasingly popular bariatric surgery procedure known as vertical sleeve gastrectomy. Using this model, we will 1) investigate how environmental and genetic CD can affect the outcome of bariatric surgery, and 2) whether and how bariatric surgery ameliorates obesity-induced changes to circadian biology. By using repeating light shifts to mirror human "night-shift work" and time-restricted feeding to mirror patients with "Night Eating Syndrome," this proposal effectively models human CD in a context that allows for mechanistic studies. Furthermore, by utilizing the Clock mutant mouse that has both circadian and metabolic impairments, this proposal also examines genetic influence on bariatric surgery success. The goals of this proposal can be achieved through a unique research training plan which integrates the investigator's expertise in circadian rhythms with new techniques, concepts, and procedures in endocrinology, metabolism, and body weight regulation. The successful execution of these proposed experiments will have two important impacts. First, it will reveal clinically relevant information as to whether individuals with CD ar less responsive to bariatric surgery. Second, by combining molecular and behavioral aspects of circadian biology with the powerful impact of bariatric surgery on multiple metabolic systems, it will shed considerable light on the key mechanisms that link circadian rhythms to metabolic diseases. This will provide insight into both the etiology of metabolic diseases as they relate to circadian biology and also potential therapeutic strategies that could mimic crucial molecular and physiological effects of bariatric procedures by less invasive and more tailored means.