Predictors of Recidivism to Obesity in Weight-Reduced Individuals

肥胖是人类疾病和医疗费用的主要贡献者，因为它与 2型糖尿病、高血压、脂肪肝、血脂异常、各种癌症、退行性脑部疾病以及 最近，与SARS-CoV-2感染相关的发病率和死亡率的贡献。适度减肥可以 缓解或完全逆转这些表型中的许多严重程度。保持10%的缩水车身 肥胖或苗条的人会在能量消耗(减少)和饥饿中引发体内平衡的变化 (增加的)倾向于恢复体重的。这些变化是通过持久的复杂分子- 大脑和自主神经系统的生理过程，甲状腺和瘦素轴，骨骼肌， 和脂肪组织。不同个体的反应强度不同，这可能解释了 长期保持减肥成功。这项研究前瞻性地检查了行为和分子水平。 超重患者通过生活方式减轻10%体重后这些系统的生理学变化 或肥胖，并检查这些因素对一年内体重恢复的贡献 在最低限度的临床干预期间实现体重减轻后。我们的特定 实验目标是： 1.研究行为、新陈代谢和环境对成功减肥10%的影响 通过测量(A)即刻能量摄入量(Ei)、(B)24小时能量消耗(EE)和(C) 一年内体重和脂肪变化对个体减重时的饮食环境的影响 在实现了10%的减重后。 2.评估动态环境中体重减轻状态的生理状态，以便提供预测因素 体重减轻10%后12个月的体重结果。将测量Ei和Ee：(A)响应于 体重减轻后单次注射瘦素；(B)体重后6个月 损失。 3.生成预测12岁以下儿童体重变化的机械信息回归方程 体重减轻10%后的几个月。与Ei和Ee相关的“内表型”将以重量- 状态降低：食物选择任务表现与食物摄入量和背部fMRI活动有关 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/暴露组学和内分泌，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， 将被用来生成预测方程，该方程将量化这些因素和 建议可能的干预措施，以帮助长期维持减轻的体重。

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.