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: 8454920
• 负责人: Deanna Marie Arble
• 金额: $ 4.92万
• 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 2014-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454920
• 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; 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. PUBLIC HEALTH RELEVANCE: This proposal is expected to provide clinically relevant advances in the treatment of obesity, particularly within the severely obese and/or circadian disrupted population, as well as insights into the mechanistic biology controlling body weight regulation.

描述（由申请人提供）：美国约有7800万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，在正常昼夜节律被打乱的人群（例如夜班工人和夜食综合征患者）中，也观察到体重增加和代谢紊乱的风险增加。目前，治疗严重肥胖和糖尿病最成功的方法是减肥手术。虽然我们知道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是什么呢