Exercise in a Pill: Key Molecules Identified that Decrease Hunger Post-Exercise

Yong Xu/Baylor University, Jonathan Long/Stanford

Yong Xu/Baylor University, Jonathan Long/Stanford

For the exercise-phobic, a pill that would create the benefits of exercise without the work has been a pipe dream. Today, such a pill – actually, an “anti-hunger molecule” – is a bit closer to reality.

For the exercise-phobic, a pill that would create the benefits of exercise without the work has been a pipe dream. Today, such a pill – actually, an “anti-hunger molecule” – is a bit closer to reality.

For those with metabolic disease, the elderly and the infirm, this advance has the potential, eventually, to provide some of the benefits of exercise in the form of protection against excessive weight gain, type 2 diabetes and other cardiometabolic diseases. Muscle strength, alas, is not included.

Researchers at Baylor College of Medicine, Stanford University and other institutions began this research to look more closely at exercise and identify the molecules and pathways associated with its benefits. In the process, they identified multiple molecules in the blood that are produced during exercise that also lower food consumption.

Writing in Nature, co-corresponding author Yong Xu, Ph.D., professor of pediatrics – nutrition and molecular and cellular biology at Baylor, and colleagues showed that “exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signaling metabolite that suppresses feeding and obesity.”

Lac-Phe is synthesized from lactate (created by strenuous exercise) and phenylalanine (which helps form protein). Biosynthesis occurs in the CNDP2+ cells, “such as macrophages, monocytes and other immune and epithelial cells localized to diverse organs,” they wrote.

In their research, a high dose of Lac-Phe caused mice who were obese because of their high-fat diets to eat approximately half as much as the control group in a 12-hour period and about 30% less than the obese mice normally ate. Their movements and energy expenditures were not affected. When the obese mice received Lac-Phe for 10 days, cumulative food intake continued to be reduced and glucose homeostasis improved.

The team put mice through their paces on a treadmill and afterward looked for spikes of certain molecules in their blood. “We wanted to let the data speak for itself,” co-corresponding author Jonathan Long, M.D., assistant professor of pathology at Stanford Medicine and an Institute Scholar of Stanford ChEM-H (Chemistry, Engineering & Medicine for Human Health), said in a statement. Of the many molecules identified, Lac-Phe was the most significant.

Long and his team then worked with veterinarians at Golden Gate Fields, a racetrack in the San Francisco Bay area, to see if Lac-Phe spiked in racehorses after races. (Blood draws after races are usual, and are used to ensure no performance-enhancing drugs are used. Long and colleagues just added one more assay.)

The results showed the same post-exercise spike in the same molecule in horses that researchers saw in mice. Long then contacted a colleague who was conducting similar studies in humans, who also noted a significant spike in Lac-Phe.

In addition to the spike in Lac-Phe, this multi-institution research team also found synergy between weight loss and the enzyme CNDP2, which catalyzes the effects of lactate and phenylalanine, thus helping to create Lac-Phe. Mice lacking the CNDP2 could not produce Lac-Phe, so they ate more than mice with normal CNDP2 activity, they reported. “We estimate that the Lac-Phe pathway is responsible for about 25% of the anti-obesity effects of exercise,” Long stated.

“We have always been interested in the regulation of feeding and body weight,” Xu told BioSpace. In an earlier statement, he explained: “Regular exercise has been proven to help weight loss, regulate appetite and improve the metabolic profile, especially for people who are overweight and obese. If we can understand the mechanism by which exercise triggers these benefits, then we are closer to helping many people improve their health.” The findings from this study are improving scientists’ understanding of the physiological processes at play at the molecular level in the relationship between exercise and hunger.

This work is in its early stages but is expected to translate well to humans. The increase in circulating levels of Lac-Phe occurs in humans and racehorses, as well as in mice, which indicates that this metabolite is a molecular effector across many types of activity and across many species of mammals. In humans, sprints were most effective in causing Lac-Phe to form, followed by resistance training and then, endurance training.

Xu is cautiously optimistic about how these findings may be applied to human health. “We really do not know whether there may be any physiologic downsides to humans of such a pill. Further studies are warranted to carefully examine therapeutic potentials and possible side-effects of Lac-Phe in humans,” he said.

Going forward, Xu continued, “We are actively searching for potential receptors that mediate Lac-Phe’s effects on feeding and body weight.” This includes research to understand which receptors in the brain are mediated by Lac-Phe so this molecule – eventually – may be used therapeutically.

Gail Dutton is a veteran biopharmaceutical reporter, covering the industry from Washington state. You can contact her at gaildutton@gmail.com and see more of her work on Muckrack.