A Pill That Triggers a Desire to Exercise? Maybe... For Now, Just Go to the Gym

By Deborah Borfitz 

September 24, 2024 | What Wegovy has done for people who want to lose weight but dislike the work involved might one day find its match with a pill that pumps up a person’s desire to exercise—all by adjusting their level of interleukin 15 (IL-15), a cytokine that in the brain stimulates locomotor activity. At least that’s one of the promising possibilities dredged up by a study in mice finding a muscle-brain pathway controlling “eagerness to train more when we exercise," according to Guadalupe Sabio, Ph.D., head of the Interaction between Organs in Metabolic Diseases Group at the Spanish National Cancer Research Centre (CNIO) in Madrid.  

To be fair, clinical trials of a seemingly magical pill are many years away, she says. But obese human volunteers were shown to have lower blood levels of IL-15 as part of the study published recently in Science Advances (DOI: 10.1126/sciadv.adn5993). 

Exercise in mice was found to activate muscle p38 gamma and thereby motivate more movement through secretion of IL-15. The protein had a direct effect on the part of the cerebral cortex that controls movement, the motor cortex, and regular exercise disproportionately ramped up its production so the mice would “run more and run faster,” Sabio says. 

P38 is a family of mitogen-activated protein kinases—alpha (α), beta, gamma (γ), and delta—which helps coordinate cellular responses to stressful stimuli, and one of the pathways known to be activated during exercise in human skeletal muscle. Paradoxically, it also promotes insulin resistance and glucose intolerance in metabolic syndrome, says Sabio. Teasing out the contrasting effects of the four family members was the study’s objective. 

What was learned is that, in lean healthy humans, both p38γ and p38α are activated in muscles that were exercised with an increasing intensity. In mice, p38α was also found to inhibit p38γ activation, which was interpreted as a possible regulatory mechanism to prevent overexertion. 

The correlation seen between p38γ activation and increased blood IL-15 levels was less pronounced among obese human participants, suggesting the potential therapeutic relevance of the muscle-brain communication pathway in treating obesity and metabolic diseases, the researchers report. If p38γ can induce production of IL-15, and thereby voluntary muscle activity, it might be possible to create an exercise-motivating drug that could help reduce the risk of diabetes and liver steatosis. 

Consequence or Cause?

In a practical sense, the discovery of the muscle-brain pathway might help explain what fitness enthusiasts have long held—working out gets easier with repeat visits to the gym. The same system that triggers the inclination to exercise more also includes a “brake” to ensure people don’t do too much exercise, says CNIO research scientist Alfonso Mora, DVM, Ph.D. 

Of course, under-exercising is more common than over-exercising in the general population with a plethora of excuses for remaining sedentary. The research team is not looking to add low IL-15 to the list. “It’s not that simple,” says Mora. 

But it was “quite surprising” to find the p38γ and p38α proteins were controlling interest in physical activity, most notably p38γ when mice were made to exercise regularly, Sabio says. Even in obese animals fed a high-fat diet, routine exercise improved their metabolism and reduced the tendency toward diabetes and fat accumulation. 

“It is going to be important to understand how these two proteins [p38γ and p38α] are activated not only in lean people, but also in obese people,” she adds. “In mice, the activation of p38 gamma was less in obese mice than lean mice, and we think it could be similar in obese people.” 

Since the obese human volunteers had lower blood levels of IL-15 than the patient controls, the protein might be responsible for a decrease in p38γ, says Cintia Folgueira, Ph.D., a researcher at the National Center for Cardiovascular Research in Madrid. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway. 

One big unknown is if less IL-15 is a “consequence or cause” of obesity, says Mora. It could be that because of abnormal accumulation of fat in the body people exercise less and therefore have lower levels of IL-15 in their blood. If so, they don’t need a pill provided they are properly motivated to get moving. 

Next Steps

Several lines of investigation are now on the table, says Sabio. One is to assess which different diseases exercise could benefit using a humanized mouse model. Another is to learn which types of exercise might induce increases in IL-15, which would help clinicians prescribe training programs for health improvement purposes. 

The more long-term idea is to collaborate with proteomics experts on the design of a peptide to mimic IL-15, she adds, providing a therapeutic option for people who need to exercise more than they are willing or able to do, she continues. Currently, no IL-15 therapies are approved for marketing, although many such drugs are in clinical trials. 

The main challenge will be finding the site in the motor cortex where communication with the p38γ protein is taking place, Sabio says, so that the agent could activate production of IL-15. Similar work is underway with peptides that mimic or enhance insulin's actions in the body as a treatment for diabetes, she notes. Longevity and aging studies evaluating the mechanisms that regulate IL-15 are also planned, Folgueira adds. 

The latest published study has certainly piqued the curiosity of readers about how fast and easy it will be to get an exercise-inducing pill on the market, and whether there will be secondary effects, says Sabio. The other commonly asked question is whether IL-15 levels are the same in people who are lean and likewise among those who are fat. This is often followed by a remark about how they don’t like to exercise, and their IL-15 may perhaps be too low for exercise alone to restore it to a healthy level. 

For Sabio, the biggest takeaway from the study should be this: “If you exercise, you will want to do more exercise.” 

Currently available technology for measuring IL-15 is “very bad,” she says, “so we think it’s important to have a reliable measurement method to be able to use it in the future.” Sabio says she imagines people will have differing levels of IL-15 that could be variably addressed by exercise or a drug, and it could in the future serve as a biomarker of progress much like diabetics manage their disease by regularly tracking their glucose levels with a finger prick test.