The drug’s exercise mimetic ability could treat obesity, diabetes, and muscle loss by activating metabolic pathways.
A groundbreaking drug, tested in mice, offers promising results for a novel weight-loss solution that replicates the effects of exercise. Developed by a University of Florida pharmacy professor and collaborators, this compound induces weight loss in obese mice by tricking their muscles into believing they are exercising more than they actually are, thereby enhancing their metabolism.
Furthermore, the drug improves endurance, enabling mice to run nearly 50% further without any physical exertion.
This drug falls under the category of “exercise mimetics,” designed to deliver some exercise benefits without requiring increased physical activity. While still in its early stages, this treatment holds potential for future human trials, targeting conditions like obesity, diabetes, and age-related muscle loss. This research follows the success of drugs like Ozempic, which revolutionized appetite control for metabolic disease treatment.
However, unlike Ozempic, the new drug, named SLU-PP-332, doesn’t impact appetite or food intake, nor does it compel mice to exercise more. Instead, it stimulates a natural metabolic pathway typically activated by exercise. Essentially, the drug deceives the body into simulating marathon training, leading to increased energy expenditure and accelerated fat metabolism.
“This compound essentially instructs skeletal muscles to undergo the same changes observed during endurance training.”
Thomas Burris, the UF pharmacy professor
“When administered to mice, the drug prompts their entire body metabolism to switch to utilizing fatty acids, mirroring what happens during human fasting or exercise. Consequently, the animals begin to lose weight.”
Burris
Burris, along with researchers from Washington University in St. Louis and St. Louis University, published their findings on September 22nd in the Journal of Pharmacology and Experimental Therapeutics.
The new drug targets a specific group of proteins within the body called ERRs, responsible for activating crucial metabolic pathways in energy-demanding tissues like muscles, the heart, and the brain. While ERRs become more active during exercise, stimulating them with drugs has proven challenging.
Building on their initial success, researchers published additional findings in March, detailing the successful design of SLU-PP-332 to stimulate ERR activity. They observed the compound’s ability to empower normal-weight mice to run 70% longer and 45% further compared to untreated counterparts.
The latest research applied the drug to obese mice. Treatment over a month resulted in 10 times less fat gain and a 12% body weight reduction compared to the control group. Remarkably, food intake and exercise levels remained unchanged.
“This translates to increased basal energy expenditure.”
Burris
Upcoming research from the Burris lab indicates the compound’s potential in treating heart failure through heart muscle strengthening in mice.
Safety assessments remain positive, with no severe side effects reported. Further development of SLU-PP-332 involves structural refinement, aiming for oral administration rather than injection. Subsequent testing in more animal models will evaluate safety before potential human trials.
Although prior attempts at developing exercise mimetics haven’t reached market due to lengthy development timelines and the inherent complexities of targeting obesity, the success of drugs like Ozempic, Wegovy, and Mounjaro (initially intended for diabetes treatment but demonstrating weight loss effects) has revitalized research and funding in this arena.
Burris highlights the drug’s potential for preserving muscle mass during weight loss (often accompanied by lean muscle loss) or during aging, a period when exercise effectiveness naturally declines. Further research is necessary to fully understand its potential.
“This holds promise for improved health maintenance throughout life.”
Burris
Abstract
Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity.
SIGNIFICANCE STATEMENT An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.