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

项目摘要/摘要 肥胖是心脏代谢性疾病的主要可改变的危险因素 影响女性。目前的行为减肥干预措施只能产生适度的体重 失败与高累犯率有关，而且女性成功的可能性较小。 进化论的考虑可以帮助整合不同的研究思路 生殖生理学和代谢生理学是相关的，并提供了重要的洞察 女性肥胖的病理生理学研究。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者， 抑制会以抑制体重的方式影响能量摄入和消耗 损失。最近，一种独特的下丘脑-垂体-卵巢功能失调 在经常骑自行车的肥胖女性中观察到了(HPO)轴， 导致促性腺激素和卵巢激素水平低于正常水平 体重超标的女人。这种失调可能非常普遍，并与 心脏代谢危险因素与不育症。虽然已经推定这种混乱 随着体重减轻而改善，促性腺激素和卵巢激素受到抑制 体重正常的女性对能量限制的反应。这种压制反映了一种 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，通过行为体重限制能量 丢失可能会延长或导致某些女性的HPO轴失调，这可能反过来 抑制体重减轻。这项拟议的研究旨在填补有关 肥胖相关HPO轴失调的患病率和病因(目标1)，检查 通过行为减肥干预改善的程度(目标2)，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， 40例绝经前肥胖妇女的纵向观察性研究 参加了由美国国立卫生研究院资助的为期一年的随机减肥试验。参赛者将接受 前一个月和前一个月完整月经周期中HPO轴功能的测量 行为减肥干预的前3个月。考德威尔博士将表演 这些措施以及在父母试验中获得的补充措施(在 体重、身体成分、心脏代谢参数、能量摄入量和能量 支出)。中心前提是新陈代谢不太健康的肥胖状态 与更严重的HPO轴失调有关；这降低了能量 行为减肥期间的可用性将延长或诱导HPO轴失调 一些女性；HPO轴失调的持续或发展将 抑制体重减轻，促进体重增加。考德威尔博士将获得实质性的职业生涯 通过开展本研究和形成批判性研究进行发展培训 支持她独特研究路线的合作。她将利用这些发现 向极具影响力的独立研究生涯过渡到开发小说 通过K01颁奖期的结束来减少肥胖的方法。 好了！

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. !