Exercise Cuts Appetite, Aids Weight Loss

Researchers have provided new insights into how exercise helps lose weight. They discovered a mechanism by which the compound Lac-Phe, which is produced during exercise, reduces appetite in mice, leading to weight loss. The findings appeared 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 researchers previously discovered that Lac-Phe is the most increased metabolite—a product of the body's metabolism—in blood after intense exercise, not just in mice but also in humans and racehorses. The team's previous work showed that giving Lac-Phe to obese mice reduced how much they ate and helped them lose weight without negative side effects. But until now, scientists didn't fully understand how Lac-Phe works to suppress appetite.

"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 studied two types of brain cells in mice. One type was AgRP neurons, which stimulate hunger and are in the arcuate nucleus of the hypothalamus. The other type was PVH neurons in the paraventricular nucleus of the hypothalamus. These neurons help suppress hunger.

AgRP and PVH neurons work together. Normally, AgRP neurons send signals that inhibit PVH neurons, making you feel hungry. But when AgRP neurons are turned off, PVH neurons become more active, reducing appetite.

He lab members and colleagues discovered that Lac-Phe directly inhibits AgRP neurons, which in turn activates PVH neurons. This chain of events resulted in mice eating less. The animals' behavior remained normal, suggesting that Lac-Phe doesn't cause unpleasant 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. 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. "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.