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

昼夜节律紊乱和减肥手术：对新陈代谢、生物钟生物学的影响

• 批准号: 8646599
• 负责人: Deanna Marie Arble
• 金额: $ 5.04万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646599
• 关键词: Address; Adult; Affect; American; Attenuated; Bariatrics; Behavioral; Biology; Body Weight; Body Weight decreased; Body fat; Body mass index; Caloric Restriction; Cardiovascular Diseases; Circadian Rhythms; Country; Data; Diabetes Mellitus; Diet; Eating; Effectiveness; Endocrinology; Etiology; Failure; Fatty acid glycerol esters; Gastrectomy; Gene Expression; Gene Mutation; Genes; Genetic; Glucose; Goals; Health; Heart Diseases; Hour; Human; Impairment; Individual; Laboratories; Lead; Light; Link; Lipids; Malabsorption Syndromes; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Morbid Obesity; Mus; Mutant Strains Mice; Mutation; Obesity; Outcome; Patients; Peripheral; Physiological; Play; Population; Positioning Attribute; Procedures; Regulation; Research Personnel; Research Training; Risk; Rodent Model; Role; Signal Transduction; Societies; Stroke; Syndrome; System; Techniques; Testing; Therapeutic; Time; Tissues; Weight Gain; bariatric surgery; blood glucose regulation; clinically relevant; compare effectiveness; feeding; improved; insight; mouse model; novel; obesity treatment; public health relevance; research study; response; shift work; success

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.

描述（由申请人提供）：大约 7800 万美国成年人被归类为肥胖，其体重指数大于 30 kg/m2。糖尿病、心脏病、中风和癌症等严重的心脏代谢健康威胁与肥胖有关。有趣的是，在正常昼夜节律被破坏的人群（例如夜班工人和夜食综合症患者）中也观察到体重过度增加和代谢紊乱的风险增加。目前，严重肥胖和糖尿病最成功的治疗方法是减肥手术。虽然众所周知，减肥手术的成功程度因人而异，但造成这种差异的确切原因 未知。鉴于约 40% 的减肥手术人群也存在一定程度的昼夜节律紊乱 (CD)，因此昼夜节律生物学紊乱可能会影响减肥手术的结果。研究昼夜节律在新陈代谢正常和失调方面所发挥的重要作用，标志着一种新的、综合的方法可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来逆转，从而阐明关键的昼夜节律和代谢联系。具体来说，该提案利用了我们实验室开发的啮齿动物模型，该模型适用于日益流行的减肥手术，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引起的昼夜节律生物学变化。通过使用重复的光移来反映人类的“夜班工作”和限时喂养来反映“夜食综合症”患者，该提案在允许进行机制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时钟突变小鼠，该提案还研究了遗传对减肥手术成功的影响。该提案的目标可以通过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、新陈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，它将揭示有关 CD 患者是否对减肥手术反应较差的临床相关信息。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个代谢系统的强大影响相结合，它将极大地揭示将昼夜节律与代谢疾病联系起来的关键机制。这将提供对与昼夜节律生物学相关的代谢疾病的病因学的深入了解，以及可以通过侵入性更小、更有针对性的手段来模拟减肥手术的关键分子和生理效应的潜在治疗策略。