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，尤其是I型子宫内膜癌

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.