Researchers at Baylor College of Medicine, Stanford School of Medicine, and collaborating institutions have identified a molecule called N-lactoyl-phenylalanine (Lac-Phe) in the blood, which is produced during exercise and can effectively reduce food intake and obesity in mice. The new findings improve our understanding of the physiological processes that underlie the interplay between exercise and hunger, and could lead to new therapeutic opportunities to effectively capture the cardiometabolic benefits of exercise for human health.

“Regular exercise has been proven to help weight loss, regulate appetite, and improve the metabolic profile, especially for people who are overweight and obese,” said Yong Xu, MD, PhD, professor of pediatrics, nutrition, and molecular and cellular biology at Baylor. “If we can understand the mechanism by which exercise triggers these benefits, then we are closer to helping many people improve their health.”

Xu is co-corresponding author of the team’s published paper in Nature, which is titled, “An exercise-inducible metabolite that suppresses feeding and obesity.”

Exercise is known to protect against obesity, type 2 diabetes, and other cardiometabolic diseases, the authors explained. But while “there has been a growing interest in identifying “molecular transducers” that might mediate the cardiometabolic benefits of exercise,” the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity aren’t clear.

“We wanted to understand how exercise works at the molecular level to be able to capture some of its benefits,” said study co-corresponding author Jonathan Long, MD, assistant professor of pathology at Stanford Medicine and an Institute Scholar of Stanford ChEM-H (Chemistry, Engineering & Medicine for Human Health). “For example, older or frail people who cannot exercise enough, may one day benefit from taking a medication that can help slow down osteoporosis, heart disease, or other conditions.”

For their reported research, Xu, Long, and their colleagues conducted comprehensive analyses of blood plasma compounds from mice following intense treadmill running. “To measure exercise-induced circulating metabolites in a global and unbiased manner, we performed both targeted and untargeted metabolomics of blood plasma from mice following an acute bout of treadmill running until exhaustion,” they explained Their analyses indicated that the most significantly induced molecule was the modified amino acid Lac-Phe. This metabolite is synthesized from lactate (a byproduct of strenuous exercise that is responsible for the burning sensation in muscles) and the amino acid phenylalanine. Interestingly, the same molecule was identified as the most significant exercise-inducible metabolite change in blood plasma taken from racehorses before and after a race.

“Lac-Phe is a poorly studied metabolite of unknown function,” the researchers continued. In fact, increases in Lac-Phe levels through exercise had been reported in a previous study, and as Xu, Long, and their collaborators reported, their metabolomics data added further context by showing that this increase was one of the most notable metabolite changes resulting from acute exercise.

Experiments in mice with diet-induced obesity further showed that a high dose of Lac-Phe suppressed food intake by about 50%, when compared with control mice, over a period of 12 hours, without affecting their movement or energy expenditure. When administered to the mice for 10 days, Lac-Phe reduced cumulative food intake and body weight (owing to loss of body fat) and improved glucose tolerance. “These data demonstrate that pharmacological administration of Lac-Phe to obese but not lean mice specifically suppresses energy intake without altering energy expenditure pathways,” the investigators noted.

They also identified an enzyme called CNDP2 that is involved in the production of Lac-Phe and showed that mice lacking this enzyme did not lose as much weight on an exercise regime as a control group of animals on the same exercise plan. “The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs,” the scientists commented.

The team separately found robust elevations in plasma Lac-Phe levels following physical activity in humans. Data from a human exercise cohort showed that sprint exercise induced the most dramatic increase in plasma Lac-Phe, followed by resistance training and then endurance training. “This suggests that Lac-Phe is an ancient and conserved system that regulates feeding and is associated with physical activity in many animal species,” Long said. The authors also commented, “These data establish Lac-Phe as one of the top exercise-regulated metabolites in humans. Distinct physical activity modalities in humans lead to different quantitative changes in circulating Lac-Phe levels that correlate with blood lactate concentration … The generation of a signaling metabolite (Lac-Phe) from a metabolic fuel (lactate) establishes a functional and biochemical coupling between the metabolic state during exercise and long-lasting endocrine signaling.

“Our next steps include finding more details about how Lac-Phe mediates its effects in the body, including the brain,” Xu said. “Our goal is to learn to modulate this exercise pathway for therapeutic interventions.” The authors further concluded, “These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance … Future work uncovering the downstream molecular and cellular mediators of Lac-Phe action in the brain may provide new therapeutic opportunities to capture the cardiometabolic benefits of physical activity for human health.”

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