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.

项目摘要/摘要 超重/肥胖通常是心脏代谢失调的出现，但可怕的进展 朝向心脏代谢疾病（例如糖尿病，心脏病）可能是有效的 使用常规的内源性大麻素系统（ECS）的方法，这是一种引人注目的治疗靶标，是遗传性的 在超重/肥胖症中。 例如胰岛素抵抗，血脂异常，内脏脂肪和高血压，但对脂肪的胃口也增加了 食物，它使EC升级和心脏代谢失调的恶性循环永存。 尽管有近20年的毒品发现和大量的Clearge Clial试验会，但仍然没有ECS医疗。 已被批准用于体重/肥胖症的治疗，主要是因为这些药物虽然高度 对心脏代谢的健康有效，导致不可接受的精神病副作用。 这项研究是为了确定有效的非药理方法来干预（即“破裂”）ECS- 持续的循环增加了食欲/体重增加，并使心脏代谢的健康状况恶化。 该提案中的目的是确定锻炼是否尤其是哪种类型的运动（例如有氧运动与有氧运动。 电阻与两者）是一种可行的方法，可减少EC的多动症并改善心脏代谢健康 超重/肥胖的成年人。 多动症，介导了有氧运动对心脏代谢健康的众所周知的好处 中央假设将通过追求两个具体目标来检验：1）确定12个月的影响 406个良好的成年人的有氧，抵抗和有氧和抵抗性的ECS 通过进行质谱和基因表达分析，以> 1200的量表进行超重/肥胖 ANN NIH资助的临床运动试验的血液标本； ECS已建立的心脏代谢风险因素（例如，血压，脂质，胰岛素抵抗）的变化， 通过进行休闲分析来应对12个月的运动训练。 创新的元素侧重于EC的多个组件（即配体，受体，酶） 新兴和不同的机制来研究运动对心脏代谢健康的多种影响，它 指南针直接可以在不同类型和安第斯山脉之间的心脏代谢健康益处和基本机制 运动的组合，特有的抵抗运动，在很大程度上被忽略了 ECS。 长期运动训练很重要，因为它可能会提供一种新颖的科学框架 可以探索和开发替代性，安全和有效的内源性药物。 这项研究通过提前个性化的临床锻炼处方（例如，推荐的模式）进行研究。 超重/肥胖的我们成年人中有三分之二以上，患有心脏代谢疾病的风险。