Rethinking Obesity and Cardiometabolic Health in Women: Using Evolutionarily Informed Hypotheses to Integrate Physiology and Behavior During Weight Loss

项目总结/摘要 肥胖是心脏代谢疾病的主要可改变风险因素，而心脏代谢疾病的比例不成比例 影响女性。目前的行为减肥干预措施只产生适度的体重 失败的再犯率很高，女性成功的可能性较小。 进化的考虑可以帮助整合不同的研究路线， 生殖和代谢生理学是相关的，并提供了重要的见解， 女性肥胖症的病理生理学。促性腺激素和卵巢激素 被认为是女性能量平衡和身体组成的关键调节器， 抑制会影响能量的摄入和消耗， 损失最近，一种独特的功能失调的下丘脑垂体卵巢 (HPO)轴已经在有规律地骑自行车（eumennorheic）的肥胖妇女中观察到， 导致促性腺激素和卵巢激素水平低于正常水平 体重的女人这种失调可能是非常普遍的，并与 心脏代谢危险因素和生育力低下。虽然人们认为这种疾病 随着体重减轻，促性腺激素和卵巢激素被抑制， 正常体重的女性对能量限制的反应。这种抑制反映了一种 适应性反应，战略性地将能量从生殖转移到 在资源稀缺的情况下生存。因此，通过行为体重来限制能量 在某些女性中，损失可能延长或诱导HPO轴失调，这反过来可能 抑制体重减轻。拟议的研究旨在填补有关知识的空白 肥胖相关HPO轴失调的患病率和病因（目的1），检查 行为减肥干预（目标2）的改善程度，并探索 这种疾病对能量摄入和消耗（包括体力活动）的影响 和久坐行为）和减肥（目标3）。研究设计是前瞻性的， 对40名健康、绝经前肥胖女性进行的纵向观察性研究 参加了一项由NIH资助的为期一年的随机减肥试验。参与者将经历 测量HPO轴功能在完整的月经周期前一个月， 行为减肥干预的前3个月。考德威尔医生将为 这些措施以及在母试验中获得的补充措施（ 体重、身体成分、心脏代谢参数、能量摄入和能量 支出）。其核心前提是，一个代谢不太健康的肥胖状态， 与更大程度的HPO轴失调相关;减少能量 行为减肥期间的可用性将延长或诱导HPO轴失调， 一些妇女; HPO轴失调的持续或发展将 抑制体重减轻和促进体重增加。考德威尔博士将获得实质性的职业生涯 通过开展这项研究和形成批判性研究， 支持她独特研究方向的合作。她将利用这些发现 过渡到一个非常有影响力的独立研究生涯， 到K 01奖励期结束时减少肥胖的方法。 !

Project Summary/Abstract Obesity is major modifiable risk factor for cardiometabolic disease that disproportionally affects women. Current behavioral weight loss interventions produce only modest weight loss with a high rate of recidivism, and are less likely to be successful in women. Evolutionary considerations can help integrate separate lines of research on how reproductive and metabolic physiology are related, and provide important insight into the pathophysiology of obesity in women. Gonadotropins and ovarian hormones are considered key regulators of energy homeostasis and body composition among women, and suppression impacts energy intake and expenditure in ways that could inhibit weight loss. Recently, a unique functional dysregulation of the hypothalamic pituitary ovarian (HPO) axis has been observed in regularly cycling (eumennorheic) women with obesity, resulting in lower levels of gonadotropins and ovarian hormones compared to normal weight women. This dysregulation may be highly prevalent and is associated with cardiometabolic risk factors and subfertility. While it has been presumed that this disorder improves with weight loss, gonadotropins and ovarian hormones are suppressed in normal weight women response to energy restriction. This suppression reflects an adaptive response to strategically shift energy away from reproduction and toward survival during resource scarcity. Therefore, restricting energy through behavioral weight loss may prolong or induce HPO axis dysregulation in some women, which may in turn inhibit weight loss. The proposed research seeks to fill gaps in knowledge regarding the prevalence and etiology of obesity-related HPO axis dysregulation (Aim 1), examine the extent to which it improves with a behavioral weight loss intervention (Aim 2), and explore the impact of this disorder on energy intake and expenditure (including physical activity and sedentary behavior), and weight loss (Aim 3). The study design is a prospective, longitudinal, observational study of 40 eumemorhheic, pre-menopausal, obese women enrolled in a NIH-funded 1-year randomized weight loss trial. Participants will undergo measures of HPO axis function over complete menstrual cycles the month prior to and the first 3 months of the behavioral weight loss intervention. Dr. Caldwell will perform these measures and those that complement them obtained in the parent trial (changes in weight, body composition, cardiometabolic parameters, energy intake, and energy expenditure). The central premise is that a less metabolically healthy obese state is associated with a greater degree of HPO axis dysregulation; that reducing energy availability during behavioral weight loss will prolong or induce HPO axis dysregulation in some women; and that the persistence or development of HPO axis dysregulation will inhibit weight loss and promote weight gain. Dr. Caldwell will gain substantive career development training through conducting this research and form critical research collaborations that support her distinctive line of research. She will leverage these findings to transition to a highly impactful independent research career developing novel approaches to reduce obesity by the conclusion of the K01 award period. !