Researchers have identified how a molecule produced during exercise curbs appetite in the brain, pointing to potential new approaches for weight control. Credit: Stock
Exercise produces Lac-Phe, which suppresses appetite by acting on brain neurons. This mechanism could inspire new weight-loss treatments.
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 work 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.”
The role of Lac-Phe
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.
“Understanding how Lac-Phe works is important for developing it or similar compounds into treatments that may help people lose weight,” He said. “We looked into the brain as it regulates appetite and feeding behaviors.”
How brain cells regulate appetite
To investigate further, the researchers examined two types of neurons in the mouse brain. AgRP neurons, located in the arcuate nucleus of the hypothalamus, stimulate hunger, while PVH neurons in the paraventricular nucleus of the hypothalamus help suppress hunger.
These two groups of neurons interact closely. Under normal conditions, AgRP neurons send inhibitory signals to PVH neurons, producing a sensation of hunger. When AgRP neurons are silenced, PVH neurons become more active, which decreases 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 behavior 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.”
Implications for weight management
This research helps explain how exercise can naturally reduce appetite and improve metabolism. “The results also suggest the exciting possibility of targeting this newly discovered mechanism for weight management,” said co-corresponding author Dr. Yong Xu, currently at the University of South Florida.
“This finding is important because it helps explain how a naturally produced molecule can influence appetite by interacting with a key brain region that regulates hunger and body weight,” said co-corresponding author Dr. Jonathan Long at Stanford University School of Medicine.
Although this study focused on mice, the findings are promising for humans. Future research will explore how Lac-Phe works in different metabolic states (like obesity vs. leanness), how it travels to the brain and whether it can be used safely and effectively as a therapy.
Reference: “Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice” by Hailan Liu, Veronica L. Li, Qingzhuo Liu, Yao Liu, Cunjin Su, Hueyxian Wong, Na Yin, Hesong Liu, Xing Fang, Kristine M. McDermott, Hueyzhong Wong, Meng Yu, Longlong Tu, Jonathan C. Bean, Yongxiang Li, Mengjie Wang, Yue Deng, Yuhan Shi, Olivia Z. Ginnard, Yuxue Yang, Junying Han, Megan E. Burt, Sanika V. Jossy, Chunmei Wang, Yongjie Yang, Benjamin R. Arenkiel, Dong Kong, Yang He, Jonathan Z. Long and Yong Xu, 16 September 2025, Nature Metabolism.
DOI: 10.1038/s42255-025-01377-9
This work was supported by grants from the USDA/CRIS (51000-064-01S, 3092-51000-062-04(B)S), American Heart Association (23POST1030352), NIH (F32DK134121, R01DK136479, R01DK136526, T32GM13854), Bio-X SIGF Graduate Student Fellowship and Texas Children’s Research Scholar funds.
