Environmental Obesogens and Weight Change in the POUNDS LOST Trial

描述(申请人提供)：这项拟议的研究将从一个新的角度探索人类肥胖和超重的发病机制--在一项前瞻性研究中，可疑工业化学品的可能影响。虽然营养过剩和久坐不动的生活方式是肥胖的公认危险因素，但其他潜在的肥胖促成因素很可能起到作用，需要澄清。被称为“肥胖源”的环境化学物质可能会扰乱体重调节。全氟化合物(PFC)是一种普遍存在的持久性化学物质，在动物模型中会干扰能量稳态。然而，由于全氟碳化合物特定物种的毒代动力学、组织分布和作用机制，动物数据与人类的相关性是不确定的。主要来自横断面研究的人类证据与PFC与较高体重相关的假设基本一致，但缺乏前瞻性数据排除了任何因果推断。因此，研究人员将在最近完成的精心设计和严格实施的减磅试验中，前瞻性地检查这些污染物与人体体重调节的作用。这项为期两年的试验的参与者包括811名男性和女性，他们被随机分配到四种低卡路里饮食中的一种。虽然饮食对体重变化的影响相似，但在短期体重下降和随后的体重回升中观察到了显著的个体间差异，这无法用遵从性或既定的肥胖风险因素来解释。研究人员将分析储存的血浆中的PFC，以检查在完成6个月和2年随访的约700名参与者中，基线PFC水平是否与较少的体重减轻和较大的体重恢复有关。此外，我们将检查试验中纵向记录的腰围和全身、腹部和肝脏的脂肪含量之间的关系。研究人员还旨在通过评估血浆PFC浓度与脂肪组织中基因表达谱以及脂肪因子和甲状腺激素的变化来阐明可能的机制。多学科研究团队由在肥胖症研究、环境流行病学、营养学、遗传学和生物统计学方面具有资格和经验的专家组成，从而确保了当前项目的成功实施。这些前瞻性证据将与人类直接相关，可能会导致对肥胖和相关疾病后果的新见解和新假设，并将有助于制定更全面和有效的肥胖预防和治疗策略。

DESCRIPTION (provided by applicant): The proposed study will explore the pathogenesis of human obesity and overweight from a new angle - the possible effects of suspected industrial chemicals in a prospective study. While over-nutrition and sedentary lifestyle are well-established risk factors of obesity, a role of other potential obesity-contributing factors is highy likely and needs to be elucidated. Environmental chemicals known as "obesogens" may upset body weight regulation. Perfluorinated compounds (PFCs) are ubiquitous, persistent chemicals that interfere with energy homeostasis in animal models. However, because of species-specific toxicokinetics, tissue distribution, and mechanisms of action of PFCs, the relevance of animal data to humans is uncertain. Human evidence originated primarily from cross-sectional studies is largely consistent with the hypothesis that PFCs are associated with higher body weight, but lack of prospective data precludes any causal inference. The investigators will, therefore, prospectively examine the roles of these pollutants in relation to human weight regulation in the well-designed and rigorously-implemented POUNDS LOST Trial that was recently completed. The participants of this 2-year trial consist of 811 men and women who were randomized to one of four calorie- reduced diets at baseline. While the diets had similar effects on weight change, substantial between-individual variability was observed in short-term weight-loss and subsequent weight-regain that cannot be explained by compliance or established obesity risk factors. The investigators will analyze banked plasma for PFCs to examine whether baseline PFC levels are associated with less weight-loss and greater weight-regain among ~700 participants who completed 6-month and 2-year follow-up. In addition, we will examine associations with waist circumference and fat content of whole body, abdomen, and liver that were longitudinally recorded in the trial. The investigators also aim to elucidate possible mechanisms by evaluating plasma PFC concentrations in regard to gene expression profiles in adipose tissue, as well as changes of adipokines and thyroid hormones. The multidisciplinary research team is comprised of experts with qualifications and experience in obesity research, environmental epidemiology, nutrition, genetics, and biostatistics, thus ensuring successful implementation of the current project. The prospective evidence will be directly relevant to humans, will likely lead to new insight and hypotheses regarding obesity and related disease outcomes, and will facilitate making more comprehensive and effective strategies for obesity prevention and treatment.