The effect of exercise on the endocannabinoid system as a pathway to cardiometabolic health in adults with overweight/obesity.

项目摘要/摘要 超重/肥胖往往先于心脏代谢紊乱的出现，然而可怕的进展 对于心脏代谢性疾病(如糖尿病、心脏病)，如果有效的话是可以避免的 调节内源性大麻素系统(ECS)的方法，ECS是一个引人注目的过度活跃的治疗靶点 超重/肥胖。ECS多动不仅导致一系列心脏代谢危险因素 如胰岛素抵抗、血脂异常、内脏脂肪和高血压，但也增加了对脂肪的胃口 食物，使不断升级的ECS过度活动和心脏代谢失调的恶性循环永久化。 尽管经过了近20年的药物发现和大规模的临床试验，仍然没有一种ECS药物可以 已被批准用于治疗超重/肥胖，主要是因为这些药物，虽然高度 对心脏代谢健康有效，导致不可接受的精神副作用。因此，长期目标是 本研究旨在找出有效的非药理学方法来干预(即“打破”)ECS- 食欲增加/体重增加和心脏代谢健康恶化的永久化循环。整体而言 本提案的目标是确定运动，特别是哪种类型的运动(例如，有氧运动与 阻力VS两者)，是减少ECS过度活动和改善心脏代谢健康的可行方法 超重/肥胖的成年人。中心假设是有氧运动，尤其是减少ECS 多动症，这是众所周知的有氧运动对心脏代谢健康的好处。这个 中心假设将通过追求两个具体目标来检验：1)确定12个月的 406名表型良好的成年人的有氧、耐力及有氧和耐力联合运动对ECS的影响 通过对1,200个仓库进行质谱分析和基因表达分析，发现超重/肥胖 来自美国国立卫生研究院资助的临床锻炼试验的血液样本；以及2)评估 已建立的心脏代谢危险因素(例如，血压、血脂、胰岛素抵抗)发生变化的ECS， 通过对12个月的运动训练进行非正式的中介分析。这个项目是 创新，因为它专注于ECS AS的多种成分(即配体、受体、酶) 研究运动对心脏代谢健康的不同影响的新兴和独特的机制，以及它 直接比较不同类型和类型之间的心脏代谢健康益处和潜在机制 锻炼的组合，特别是抵抗力锻炼，这在很大程度上被忽视了 欧洲中央情报局。这是对ECS适应不同类型的 长期运动训练意义重大，因为它可能提供一种新的科学框架， 可以探索和开发替代的、安全的和有效的内源性大麻素药物。此外， 这项研究将推进个性化的临床运动处方(例如，推荐的方式) 在超重/肥胖的美国成年人中，超过三分之二的人面临心脏代谢性疾病的风险。

PROJECT SUMMARY/ABSTRACT Overweight/obesity often precedes the emergence of cardiometabolic dysregulation, yet the dire progression toward cardiometabolic diseases (e.g., diabetes, heart disease) could be averted if there were effective approaches to regulate the endocannabinoid system (ECS), a compelling therapeutic target that is hyperactive in overweight/obesity. ECS hyperactivity not only contributes to a constellation of cardiometabolic risk factors like insulin resistance, dyslipidemia, visceral fat, and high blood pressure, but also increased appetite for fatty foods, which perpetuates a vicious cycle of escalating ECS hyperactivity and cardiometabolic dysregulation. Despite nearly 20 years of drug discovery and large clinical trial efforts, there are still no ECS medications that have been approved for the treatment of overweight/obesity, mainly because these medications, while highly effective for cardiometabolic health, cause unacceptable psychiatric side effects. Thus, the long-term goal of this research is to identify effective, non-pharmacological approaches to intervene in (i.e., “break”) the ECS- perpetuated cycle of increased appetite/weight gain and worsening cardiometabolic health. The overall objective in this proposal is to determine whether exercise, specifically what type of exercise (e.g., aerobic vs. resistance vs. both), is a viable approach to reduce ECS hyperactivity and improve cardiometabolic health in adults with overweight/obesity. The central hypothesis is that aerobic exercise, in particular, reduces ECS hyperactivity, which mediates the well-known benefits of aerobic exercise on cardiometabolic health. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the effects of 12 months of aerobic, resistance, and combined aerobic and resistance exercise on the ECS in 406 well-phenotyped adults with overweight/obesity by performing mass spectrometry and gene expression analysis on >1,200 stored blood specimens from an NIH-funded clinical exercise trial; and 2) Evaluate the relationship of changes in the ECS with changes in established cardiometabolic risk factors (e.g., blood pressure, lipids, insulin resistance), in response to 12 months of exercise training by performing a casual mediation analysis. This project is innovative because it focuses on multiple components (i.e., ligands, receptors, enzymes) of the ECS as emerging and distinct mechanisms to study the diverse effects of exercise on cardiometabolic health, and it directly compares the cardiometabolic health benefits and underlying mechanisms among different types and combinations of exercise, particularly resistance exercise, which has been largely overlooked with regard to the ECS. This comprehensive, mechanistic investigation of ECS adaptations in response to different types of long-term exercise training is significant because it is likely to offer a novel scientific framework from which alternative, safe, and effective endocannabinoid medications can be explored and developed. Furthermore, this research will advance individualized clinical exercise prescriptions (e.g., recommended modality) for the more than two-thirds of US adults with overweight/obesity who are at-risk for cardiometabolic disease.