Predictors of Recidivism to Obesity in Weight-Reduced Individuals

肥胖症是人类疾病和医疗保健费用的主要贡献者，因为它与肥胖症的功能相关。 2型糖尿病、高血压、脂肪肝、血脂异常、各种癌症、退行性脑病， 最近，与SARS-CoV-2感染相关的发病率和死亡率的贡献。适度的减肥可以 减轻严重性-或完全逆转-这些表型中的许多。保持10%的身体减少， 肥胖或瘦的个体引起能量消耗（减少）和饥饿的稳态变化 （增加）倾向于恢复体重。这些变化是由持久的复杂分子传递的- 脑和自主神经系统中的生理过程，甲状腺和瘦素轴，骨骼肌， 和脂肪组织。个体在这些反应的强度上有所不同，这可能是 长期保持减肥成功。本研究前瞻性地检查了 这些系统的生理学在超重个体的生活方式介导的10%体重减轻后 或肥胖，并检查这些因素对一年内体重恢复量的贡献 在最小临床干预期间实现体重减轻后。我们的具体 实验目的是： 1.检查行为，代谢和环境对成功维持10%体重减轻的影响 通过测量（a）随意能量摄入（EI）、（B）24小时能量消耗（EE）和（c） 体重减轻时个体的饮食环境对体重和脂肪量变化的影响 在实现10%的重量减轻之后。 2.评估动态情况下减重状态的生理学，以提供预测指标 体重减轻10%后12个月的体重结果。EI和EE将被测量：（a）响应于 在体重减轻后给予单剂量的瘦素;（B）体重减轻后6个月 损失 3.生成基于机械原理的回归方程，预测12岁儿童的体重变化 体重减轻10%后的几个月。与EI和EE相关的“内表型”将以体重来测量- 减少状态：食物选择任务表现与食物摄入和背侧fMRI活动相关 纹状体;睡眠/昼夜节律;骨骼肌收缩效率（体内和体外），血浆 代谢组学/代谢组学和内分泌，尿儿茶酚胺，基因表达和表观遗传学 脂肪组织和肌肉以及外周血单核细胞。这些内表型，EI和EE， 将用于生成预测方程，该方程将量化这些因素的相对贡献， 建议可能的干预措施，以帮助长期维持体重减轻。

Obesity is a major contributor to human illness and health care costs by virtue of its functional associations with type 2 diabetes, hypertension, fatty liver, dyslipidemias, various cancers, degenerative brain disease and, very recently, contribution to morbidity and mortality associated with SARS-CoV-2 infection. Modest weight loss can mitigate the severity – or entirely reverse - many of these phenotypes. Maintenance of a 10% reduced body in obese or lean individuals invokes homeostatic changes in energy expenditure (decreased) and hunger (increased) that tend to restore body weight. These changes are conveyed by persistent complex molecular- physiological processes in the brain and autonomic nervous systems, thyroid and leptin axes, skeletal muscle, and adipose tissue. Individuals differ in the intensity of these responses, perhaps accounting for differences in long-term success for weight loss maintenance. This study prospectively examines the behavioral and molecular physiology of these systems following a lifestyle-mediated 10% weight reduction in individuals with overweight or obesity, and examines the contributions of these factors to amount of weight regain in the one year period following achievement of the weight reduction during a period of minimum clinical intervention. Our Specific Experimental Aims are to: 1. Examine the behavioral, metabolic, and environmental impacts on success in sustaining 10% weight loss by measuring the association of (a) ad lib energy intake (EI), (b) 24h energy expenditure (EE); and (c) the individual’s food environment at reduced body weight on changes in body weight and fat mass one year following achievement of 10% weight reduction. 2. Assess the physiology of the weight-reduced state in dynamic circumstances in order to provide predictors of weight outcome at 12 months after 10% weight loss. EI and EE will be measured: (a) in response to a single dose of leptin administered after achievement of reduced body weight; (b) 6 months following weight loss. 3. Generate mechanistically-informed regression equations predicting change in body weight in the 12 months following 10% weight loss. “Endophenotypes” related to EI and EE will be measured in the weight- reduced state: food-choice task performance associated with food intake and fMRI activity in the dorsal striatum; sleep/circadian rhythms; skeletal muscle contractile efficiency (in vivo and ex vivo), plasma metabolomics /exposomics and endocrines, urinary catecholamines, gene expression and epigenetics of adipose tissue and muscle, and peripheral blood mononuclear cells. These endophenotypes, EI and EE, will be used to generate predictive equations that will quantify the relative contributions of these factors and suggest possible interventions to assist in long-term maintenance of reduced body weight.