Aging and meal timing interact to exaggerate weight gain

描述(申请人提供)：大约5900万美国成年人被归类为肥胖，身体质量指数(BMI)大于30公斤/平方米。与肥胖相关的严重心脏代谢健康威胁(如糖尿病、心脏病、中风)威胁着大约30%的美国人口。老龄化人口可能面临特别的风险，因为超过50%的中年人预计会增加超重。有趣的是，在昼夜节律不同步的人群(例如，夜班工人和其他健康的、不吃早餐的人)中也观察到超重增加和代谢紊乱的风险增加。研究昼夜节律、衰老和体重之间的相互作用是一种新的探索途径。广泛地说，这项建议研究了导致老龄化和昼夜节律不同步人群体重增加的环境和遗传交互作用，以及预防其可能的治疗干预。具体地说，这一建议利用了一种创新的环境方案(即去同步摄食，DF)，该方案导致了昼夜节律光周期和代谢表达之间的错位。然后将这种环境干预应用于不同年龄的遗传模型(即C57BL/6J和Clock突变小鼠)，以确定与年龄和DF相关的导致体重增加的基因-环境交互作用。使用这种方法，这项建议调查了三个具体的假设：1)年龄和DF相加地影响能量消耗，2)年龄可以夸大DF期间的代谢损伤，3)DF改变了脑组织和外周组织的生物钟和代谢基因的表达。这项建议的目标可以通过一个严格的研究培训计划来实现，该计划侧重于整合分子技术、遗传学和体重和新陈代谢的生理测量。这项提议旨在揭示导致体重增加的新机制，并有望带来新的见解和治疗方法，旨在治疗和预防所有年龄段的肥胖症、糖尿病和其他心脏代谢紊乱，以及在昼夜节律不同步的人群中。 公共卫生相关性： 这项提议有望带来新的见解和治疗方法，旨在治疗和预防肥胖、糖尿病和其他心脏代谢紊乱，在这些疾病中，老年人和昼夜节律失调的人群特别容易受到伤害。

DESCRIPTION (provided by applicant): About 59 million American adults are classified as obese, with a body mass index (BMI) greater than 30 kg/m2. Serious cardiometabolic health threats linked to obesity (e.g. diabetes, heart disease, stroke) threaten about 30% of the American population. The aging population may be at particular risk, as over 50% of middle aged adults are expected to gain excess weight. Interestingly, excess weight gain and an increased risk for metabolic disorders is also observed in the circadian desynchronized population (e.g. night shift workers and otherwise healthy, non-breakfast eaters). Investigating the interaction between circadian rhythms, aging and body weight is a new avenue for exploration. Broadly, this proposal studies the environmental and genetic interactions which lead to weight gain in the aging and circadian desynchronized population and possible therapeutic interventions for its prevention. Specifically, this proposal utilizes an innovative, environmental protocol (i.e. desynchronized feeding, DF) which causes a misalignment between the circadian light cycle and metabolic expression. This environmental intervention is then applied to genetic models (i.e. C57BL/6J and Clock mutant mice) of varying ages to determine the gene-environment interactions leading to weight gain associated with age and DF. Using this approach, this proposal investigates three specific hypotheses: 1) that age and DF additively affect energy expenditure, 2) that age can exaggerate metabolic impairments during DF, and 3) that DF alters circadian clock and metabolic gene expression in brain and peripheral tissues. The goals of this proposal can be achieved through a rigorous research training plan which focuses on integrating molecular techniques, genetics, and physiological measurements of body weight and metabolism. This proposal aims to uncover new mechanisms leading to weight gain and is expected to lead to new insights and therapeutic approaches designed for the treatment and prevention of obesity, diabetes and other cardiometabolic disorders all age groups as well as in the circadian desynchronized population. PUBLIC HEALTH RELEVANCE: This proposal is expected to lead to new insights and therapeutic approaches designed for the treatment and prevention of obesity, diabetes and other cardiometabolic disorders in which the aged and circadian desynchronized population are particularly vulnerable.