A new study involving researchers from Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Stanford University School of Medicine, and other institutions has identified a mechanism by which exercise may contribute to weight loss. The findings 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 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 team found that Lac-Phe, a compound produced during intense exercise, reduces appetite in mice. Previous research showed that Lac-Phe levels rise significantly after intense physical activity not only in mice but also in humans and racehorses. Earlier studies by the same group demonstrated that administering Lac-Phe to obese mice decreased their food intake and led to weight loss without negative side effects.
“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.”
The researchers focused on two types of neurons in the mouse brain: AgRP neurons, which promote hunger, and PVH neurons, which suppress it. Normally, AgRP neurons inhibit PVH neurons to increase hunger signals. When AgRP neurons are less active, PVH neurons become more active, leading to reduced appetite.
According to their findings, Lac-Phe directly inhibits AgRP neurons. This inhibition activates PVH neurons and results in lower food intake among mice without affecting their normal behavior.
Further investigation revealed that Lac-Phe acts on KATP channels—proteins on AgRP neurons involved in regulating cell activity. “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.”
“This research helps explain how exercise can naturally reduce appetite and improve metabolism,” said Dr. Yong Xu from University of South Florida. “The results also suggest the exciting possibility of targeting this newly discovered mechanism for weight management.”
“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,” added Dr. Jonathan Long at Stanford University School of Medicine.
While these experiments were conducted with mice, researchers say future studies will examine how Lac-Phe functions under different metabolic conditions—such as obesity versus leanness—and whether similar effects occur in humans.
Contributors to this research included scientists from Baylor College of Medicine, Stanford University School of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, University of Texas Health Center at Houston, Boston Children’s Hospital and Harvard Medical School, as well as University of South Florida.
Funding was provided by several organizations including 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.
