Revving-Up Exercise for Sustained Weight-Loss by Altering Neurological Reward & D

描述（由申请人提供）：肥胖是我国最大的公共卫生挑战之一，也是子宫内膜癌（EC）的主要危险因素，特别是I型 形式，这是越来越多的。虽然大多数癌症的死亡率一直在下降，但EC患者的总体死亡率正在上升。EC幸存者肥胖率很高（38%-65%），肥胖的EC患者在所有癌症中死亡风险最高。与其他癌症幸存者不同，EC幸存者通常不会在癌症诊断的“可教时刻”自发改变生活方式。EC幸存者的健康水平差和手术治疗可能使减肥特别具有挑战性。然而，只有两个以前的生活方式干预集中在EC幸存者。在动物中，高强度运动已被证明通过改变纹状体多巴胺来增加神经营养因子和奖励。在人类中，长期高强度运动增强了膳食饱腹感，并可能减少享乐性饮食。我们已经证明，“辅助”运动，一种运动模式，其中患者的自愿运动率被机械地增强，改善运动控制，并具有与帕金森病患者的大脑多巴胺水平的调节一致的激活模式。在一项可行性研究中，我们评估了肥胖EC幸存者的“辅助”运动模式，发现“辅助”运动改善了健身水平，身体成分，运动动机和饮食行为。以前没有研究评估过“辅助”运动对任何人群食欲行为的影响。我们提出了一个新的跨学科的随机试验，以评估6个月的“辅助”和自愿率运动的生理和行为的结果，以及神经元活动的肥胖EC幸存者的食物线索的影响。总体目标是表明，与进行自愿运动的患者相比，进行“辅助”运动的肥胖EC幸存者将改善饮食行为，运动动机和生活质量（QoL），以及减少与食物奖励和动机相关的大脑区域中的神经元激活，以响应高热量食物图像。在具体目标1中，我们将在基线、治疗结束（EOT）和EOT后24周（EOT+24）时，评价随机分配接受24次“辅助”或自愿速率自行车运动的肥胖EC患者的生理（体重、体脂、健身）和行为（饮食行为、运动动机、QoL）变化。在具体目标2中，我们将在基线、EOT和EOT+24时进行“辅助”或自愿速率运动的肥胖EC患者中，使用功能性磁共振成像评价与奖励、动机和抑制控制相关的脑区中对高热量食物图像和停止信号任务的神经元反应。在具体目标3中，我们将评估循环中性粒细胞的变化（例如，BDNF）和脂肪因子（例如，瘦素）。拟议的“辅助”运动干预有可能导致肥胖EC患者以及其他患有或不患有癌症的肥胖个体的生存率提高。

DESCRIPTION (provided by applicant): Obesity is one of the greatest public health challenges of our nation and a leading risk factor for endometrial cancer (EC), particularly Type I forms, that are increasing. Although death rates from most cancers have been decreasing, overall mortality in EC patients is increasing. EC survivors have a high rate of obesity (38 percent-65 percent) and, obese EC patients have the highest risk of death among all cancers. Unlike other cancer survivors, EC survivors do not typically make spontaneous lifestyle changes during the 'teachable moment' of a cancer diagnosis. EC survivors' poor fitness levels and surgical treatments may make weight loss particularly challenging. However, only two prior lifestyle interventions have focused on EC survivors. In animals, high intensity exercise has been show to increase neurotrophins and reward via altered striatal dopamine. In humans, chronic high intensity exercise enhances meal satiety and may reduce hedonic eating. We have shown that 'assisted' exercise, a mode of exercise whereby the patients' voluntary exercise rate is augmented mechanically, improves motor control and has activation patterns consistent with modulation of brain dopamine levels in Parkinson's Disease patients. In a feasibility study, we evaluated the 'assisted' exercise paradigm in obese EC survivors and found that 'assisted' exercise improves fitness levels, body composition, exercise motivation and eating behavior. No prior studies have evaluated the effects of 'assisted' exercise on appetitive behavior in any population. We propose a novel transdisciplinary randomized trial to evaluate the effects of six months of 'assisted' and voluntary rate exercise on physiological and behavioral outcomes as well as neuronal activity in response to food cues in obese EC survivors. The overarching goal is to show that obese EC survivors performing 'assisted' exercise will have improved eating behavior, exercise motivation and quality of life (QoL) as well as reduced neuronal activation in brain regions associated with food reward and motivation in response to high-calorie food images compared to patients performing voluntary rate exercise that will be sustained after the intervention. In Specific Aim 1, we will evaluate physiological (weight, body fat, fitness) and behavioral (eating behavior, exercise motivation, QoL) changes in obese EC patients randomized to perform 24 'assisted' or voluntary rate cycling at baseline, end of treatment (EOT) and 24 weeks post-EOT (EOT+24). In Specific Aim 2, we will evaluate neuronal response to high-calorie food images and a stop signal task in brain regions associated with reward, motivation and inhibitory control using functional magnetic resonance imaging in obese EC patients performing 'assisted' or voluntary rate exercise at baseline, EOT and EOT+24. In Specific Aim 3, we will evaluate changes in circulating neutrophins (e.g., BDNF) and adipokines (e.g., leptin) in both groups at baseline, EOT and EOT+24. The proposed 'assisted' exercise intervention has the potential to lead to improved survival in obese EC patients as well as other obese individuals with and without cancer.