Research Project
10353234
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.
