Scientists have found out exactly how an exercise-triggered molecule suppresses hunger signals in the brain, leading to weight loss. And the good news is that it could be harnessed as a therapeutic, providing the same benefits without the hard work it takes to produce it naturally.
Researchers led by scientists at Baylor College of Medicine (BCM) have unraveled just how an exercise-induced signaling metabolite, N-lactoyl-phenylalanine (Lac-Phe), travels a unique pathway to the brain and impacts the activity of one, and then two different neurons. It triggers a chain of events that ultimately suppresses appetite – something we’ve known Lac-Phe can do, but until now we didn’t know just how.
“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, an assistant professor at BCM. “Exercise helps lose weight by increasing the amount of energy the body uses; however, it is likely that other mechanisms are also involved.
“Understanding how Lac-Phe works is important for developing it or similar compounds into treatments that may help people lose weight,” he added. “We looked into the brain as it regulates appetite and feeding behaviors.”
Lac-Phe is the metabolite that’s most increased after intense bouts of exercise, and it’s seen in humans, mice and racehorses. The researchers previously found that giving added Lac-Phe to mice reduced their food intake without any negative side effects, showing that the signaling molecule still worked as if the body had produced it naturally through exercise.
In this latest work, the team looked at two brain cells in mice – agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus, which stimulate hunger, and paraventricular nucleus (PVN) neurons in the paraventricular nucleus of the hypothalamus, which help dial down hunger signals. The two neurons form a system where AgRP neuronal signals inhibit PVH neurons, activating hunger. But when AgRP neurons are switched off, PVH neurons become more active, suppressing appetite.
Lac-Phe, the team discovered, directly blocks AgRP neurons – which boosts the activity of the PVH neurons – via a specific ATP-sensitive potassium channel (KAPT channel).
“We found that Lac-Phe acts on a protein on AgRP neurons called KATP channel, which helps regulate cell activity,” said He. “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.”
Intensive exercise – such as sprints or weight training – most effectively boost Lac-Phe activity, however, moderate workouts like endurance cycling also cause it to spike. However, as the researchers noted, this discovery opens up the possibility of using Lac-Phe as a supplement that could trigger this appetite-suppressing mechanism without the effort it takes to make it naturally.
“The results also suggest the exciting possibility of targeting this newly discovered mechanism for weight management,” said co-corresponding author Dr. Yong Xu, a researcher at the University of South Florida.
While the discovery was made in mice, and will need to be tested in humans to see if the effect is just as significant, it has the potential to be a new avenue for weight management that doesn’t appear to come with the kind of gastrointestinal stress of drugs like GLP-1 receptor agonists.
“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, a researcher at Stanford University School of Medicine.
The research was published in the journal Nature Metabolism.
Source: Baylor College of Medicine
