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

描述(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)，特别是I型子宫内膜癌的主要危险因素 形式，这些形式正在增加。尽管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幸存者的肥胖率很高(38%-65%)，在所有癌症中，肥胖的EC患者死亡风险最高。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”自发地改变生活方式。EC幸存者糟糕的健康水平和手术治疗可能会使减肥变得特别困难。然而，之前只有两次生活方式干预集中在EC幸存者身上。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，长期的高强度运动会增强饮食饱腹感，并可能减少享乐主义饮食。我们已经证明，“辅助”运动是一种锻炼模式，通过这种模式，患者的自愿运动率被机械地增加，改善了运动控制，并具有与帕金森氏症患者脑多巴胺水平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”锻炼模式，发现“辅助”锻炼改善了健康水平、身体成分、锻炼动机和饮食行为。此前没有任何研究评估过“辅助”锻炼对任何人群的食欲行为的影响。我们提出了一项新的跨学科随机试验，以评估六个月的“辅助”和自愿速率运动对肥胖EC幸存者的生理和行为结果以及对食物提示做出反应的神经元活动的影响。主要目标是表明，与接受干预后持续的自愿速率锻炼的患者相比，接受辅助性锻炼的肥胖EC幸存者将改善饮食行为、锻炼动机和生活质量(QOL)，并减少大脑中与食物奖励和动机相关的神经元激活，以应对高卡路里食物图像。在具体目标1中，我们将评估肥胖EC患者的生理(体重、体脂、健康)和行为(饮食行为、运动动机、QOL)的变化，这些患者随机在基线、治疗结束(EOT)和EOT后24周(EOT 24)进行24‘辅助’或自愿速率循环。在具体目标2中，我们将使用功能磁共振成像技术评估肥胖EC患者对高卡路里食物图像和与奖励、动机和抑制控制相关的大脑区域的停止信号任务的反应，这些患者在基线、EOT和EOT 24条件下进行“辅助”或自愿速率运动。在具体目标3中，我们将评估两组在基线、EOT和EOT 24时循环中性粒细胞因子(例如，BDNF)和脂肪因子(例如，瘦素)的变化。拟议的“辅助”运动干预有可能提高肥胖EC患者以及其他患有和不患有癌症的肥胖者的存活率。

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.