Researchers from Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, Stanford University School of Medicine, and partner institutions have uncovered a new explanation for how exercise promotes weight loss.

Their research revealed that Lac-Phe, a compound generated during physical activity, decreases appetite in mice and contributes to weight reduction. The results were published in Nature Metabolism.

“Regular exercise is considered a powerful way to lose weight and to protect from obesity-associated diseases, such as diabetes or heart conditions,” said co-corresponding author Dr. Yang He, assistant professor of pediatrics–neurology at Baylor and investigator at the Duncan NRI. “Exercise helps lose weight by increasing the amount of energy the body uses; however, it is likely that other mechanisms are also involved.”

Earlier research showed that Lac-Phe is the metabolite that rises the most in the bloodstream after vigorous exercise, a pattern observed not only in mice but also in humans and racehorses. The same team previously demonstrated that giving Lac-Phe to obese mice reduced their food intake and promoted weight loss without harmful side effects. However, the mechanism by which Lac-Phe suppresses appetite was not well understood until now.

To investigate further, the researchers examined two types of neurons in the mouse brain: AgRP neurons, located in the arcuate nucleus of the hypothalamus, which stimulate hunger; and PVH neurons in the paraventricular nucleus, which help suppress hunger.

Under normal conditions, AgRP neurons send inhibitory signals to PVH neurons, creating a sensation of hunger. When AgRP neurons are silenced, PVH neurons become more active, reducing appetite.

The team found that Lac-Phe acts directly on AgRP neurons, suppressing their activity and thereby allowing PVH neurons to become more active. As a result, the mice consumed less food. Importantly, their overall behaviour remained unchanged, suggesting that Lac-Phe reduces appetite without causing negative side effects.

In addition, the team investigated how Lac-Phe inhibits AgRP neurons. “We found that Lac-Phe acts on a protein on AgRP neurons called KATP channel, which helps regulate cell activity. “When Lac-Phe activates these channels in AgRP neurons, the cells become less active,” He said. “When we blocked the KATP channels using drugs or genetic tools, Lac-Phe no longer suppressed appetite. This confirmed that the KATP channel is essential for Lac-Phe’s effects.”

Although the study focused on mice, the researchers described the findings as promising for humans. Future research will explore how Lac-Phe functions in different metabolic states, such as obesity and leanness, how it travels to the brain, and whether it can be developed into a safe and effective therapy.