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.
