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Exercise-Mimicking Drug Helps Mice Lose Weight and Boost Endurance

Workout equipment.
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A new study has detailed the potential of a new drug to mimic the beneficial effects of exercise in mouse models. The drug – SLU-PP-332 – induced weight loss and improved endurance in obese mice, enabling them to run 50% further and lose 12% of their body weight. The research is published in the Journal of Pharmacology and Experimental Therapeutics.

Developing an exercise mimetic

The development of weight loss drugs has been fraught with difficulty due to the complexity of obesity, but new drugs such as semaglutide are now successfully helping to treat diabetes and manage weight loss. Interest in treating these metabolic diseases using other pathways has now surged, and research into developing drugs that recreate the positive effects of exercise on the body – known as exercise mimetics – has also been gathering traction. Now, researchers from the University of Florida have investigated a new candidate exercise mimetic.

The effects of the drug, called SLU-PP-332, were previously investigated in a study of normal-weight mice. The researchers found that the drug enabled mice to run for 70% longer in duration and 45% further. SLU-PP-332 boosts the activity of a group of proteins called estrogen-related receptors (ERRs), whose activity increases during exercise. ERRs are also found at high levels in tissues that demand high amounts of energy, such as the muscles, heart and brain.

In their latest research, the team expanded their study to obese mice to investigate its effects as a potential exercise-mimicking drug.

Increased endurance and weight loss

The researchers treated mice with diet-induced obesity with either SLU-PP-332 or a control solution. Seven male mice were allocated to each group and then treated with either the drug or control solution twice a day over the course of a month. The treated animals gained approximately 10 times less fat than the control mice and lost 12% of their body weight compared to the start of the study, despite no significant changes in food intake or physical activity.

“They use more energy just living,” said the study’s senior author Thomas Burris, a professor of pharmacodynamics at the University of Florida.

“This may be able to keep people healthier as they age,” he added.

Appetite, food intake and exercise are unaffected by the drug – instead, it boosts a natural metabolic pathway that typically responds to exercise, making the body act like it is undergoing physical training. This leads to increased energy expenditure and faster metabolism.

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The drug also gave the mice’s endurance a boost, helping them to run nearly 50% further than they could previously.

“This compound is basically telling skeletal muscle to make the same changes you see during endurance training,” Burris explained. “When you treat mice with the drug, you can see that their whole-body metabolism turns to using fatty acids, which is very similar to what people use when they are fasting or exercising.”

Pre-clinical findings must be explored further

The researchers did not detect any severe side effects during the mouse study. Next, they plan to refine the structure of SLU-PP-332 to aid its development as a drug and make it suitable to be formulated as a pill instead of an injection. Additionally, further studies using more animal models to test for rare side effects are required before a move toward human trials.

Burris explains that the drug has the potential to maintain muscle mass during weight loss or aging, when the body naturally has a lower response to exercise – however, it will take more research to understand its effects in more detail.

Reference: Billon C, Schoepke E, Avdagic A, et al. A synthetic ERR agonist alleviates metabolic syndrome. J Pharmacol Exp Ther. 2023. doi: 10.1124/jpet.123.001733

This article is a rework of a press release issued by the University of Florida. Material has been edited for length and content.