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

运动对内源性大麻素系统的影响作为超重/肥胖成人心脏代谢健康的途径。

• 批准号: 10353234
• 负责人: Angelique Gabrielle Brellenthin
• 金额: $ 22.14万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353234
• 关键词: Address; Adult; Aerobic; Aerobic Exercise; Blood Pressure; Blood specimen; Body Weight; Body Weight decreased; Brain; Cardiac; Cardiometabolic Disease; Clinical; Clinical Trials; Data; Data Analyses; Desire for food; Development; Diabetes Mellitus; Digestive System Disorders; Dyslipidemias; Endocannabinoids; Energy Intake; Enzymes; Exercise; Food; Foundations; Funding; Gene Expression Profiling; Goals; Health; Health Benefit; Health Care Costs; Heart Diseases; Hyperactivity; Hypertension; Individual; Insulin Resistance; Investigation; Kidney Diseases; Lead; Life Style Modification; Ligands; Lipids; Lipolysis; Maintenance; Mass Spectrum Analysis; Mediating; Mediation; Medication Systems; Mental Depression; Metabolic; Metabolic dysfunction; Metabolic syndrome; Modality; Obesity; Overweight; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiological Processes; Public Health; Research; Resistance; Rest; Rewards; Risk Factors; Role; System; Testing; Time; United States National Institutes of Health; Vascular remodeling; Visceral fat; Weight; Weight Gain; adherence rate; adult obesity; base; cardiometabolic risk; cardiometabolism; clinically significant; comorbidity; comparative; disease diagnosis; drug discovery; endogenous cannabinoid system; exercise prescription; exercise training; glucose uptake; hedonic; hemodynamics; improved; increased appetite; innovation; large datasets; middle age; novel; pleasure; receptor; receptor expression; resistance exercise; response; secondary analysis; side effect; therapeutic target

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.

项目总结/摘要 超重/肥胖通常先于心脏代谢失调的出现，但可怕的进展 针对心脏代谢疾病（例如，糖尿病，心脏病），如果有有效的 调节内源性大麻素系统（ECS）的方法，ECS是一个非常活跃的引人注目的治疗靶点 超重/肥胖。ECS活动过度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，而且还增加了对脂肪的食欲。 食物，这使ECS过度活跃和心脏代谢失调的恶性循环不断升级。 尽管近20年的药物发现和大型临床试验的努力，仍然没有ECS药物， 已经被批准用于治疗超重/肥胖，主要是因为这些药物，而高度 对心脏代谢健康有效，导致不可接受的精神副作用。长期目标是 该研究是为了鉴定有效的、非药物的方法来干预（即，“打破”）ECS- 食欲增加/体重增加和心脏代谢健康恶化的永久循环。整体 该建议的目的是确定是否进行锻炼，具体地说是什么类型的锻炼（例如，有氧运动与 抵抗与两者），是一种可行的方法，以减少ECS多动和改善心脏代谢健康， 超重/肥胖的成年人。核心假设是，有氧运动，特别是，减少ECS 多动，这介导了众所周知的有氧运动对心脏代谢健康的好处。的 中心假设将通过追求两个具体目标进行测试：1）确定12个月的影响， 有氧运动、抗阻运动以及有氧运动和抗阻运动联合对406名表型良好的成年人ECS的影响 通过对超过1，200名储存的超重/肥胖症患者进行质谱分析和基因表达分析， 来自NIH资助的临床运动试验的血液标本;和2）评估 已确定的心脏代谢风险因素发生变化的ECS（例如，血压、血脂、胰岛素抵抗）， 通过执行临时调解分析来响应12个月的锻炼训练。这个项目是 创新是因为它关注多个组件（即，配体、受体、酶）作为 新兴的和独特的机制来研究运动对心脏代谢健康的不同影响， 直接比较不同类型之间的心脏代谢健康益处和潜在机制， 运动的组合，特别是阻力运动，这在很大程度上被忽视， 的ECS。这项针对不同类型的ECS适应的全面、机制研究 长期的运动训练是重要的，因为它可能提供一个新的科学框架， 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，委员会认为， 该研究将推进个体化的临床锻炼处方（例如，建议的方式） 超过三分之二的超重/肥胖的美国成年人有心脏代谢疾病的风险。