CNDP2

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.

Researchers from the Baylor College of Medicine, part of the Stanford School of Medicine, discovered a molecule produced during exercise in mice that suppresses feeding and obesity. The results of the study were published in Nature on Wednesday. The Centers for Disease Control and Prevention reports that the prevalence of obesity in the U.S. is 41.9%. Obesity can lead to severe health conditions, including heart disease, stroke, Type II Diabetes and some types of cancer, all of which can lead to premature death. Historically, physicians and health agency officials have recommended exercise to combat and prevent obesity. The CDC recommends that people working on weight management should work their way up to 150 minutes of moderate-intensity aerobic activity, 75 minutes of vigorous-intensity aerobic exercise or an equivalent mix of both to maintain weight, with diet adjustments recommended for those looking to lose weight. And to no one's surprise, researchers overarchingly have found that physical activity increases energy expenditure and decreases total body fat, leading to weight loss. However, researchers have aimed to understand the process of exercise at a molecular level to perhaps one day harness that process as a potential therapeutic. Corresponding authors Jonathan Long, M.D., and Yong Xu, Ph.D., reported in Nature that their team discovered an exercise-inducible metabolite known as N-lactoyl-phenylalanine (Lac-Phe) that suppresses feeding and obesity in mice models. The researchers analyzed blood plasma compounds from mice that participated in intense treadmill running. They found that the most significantly-induced molecule during the exercise period was Lac-Phe. Lac-Phe is synthesized from lactate, which is produced during strenuous exercise, and phenylalanine, a building block of protein. Later, the team replicated these findings in both racehorses and humans, leading the researchers to conclude that metabolite is part of a system that regulates feeding, influences systemic energy balance and is associated with physical activity in many species. Taking their findings a step further, the researchers then used mice with diet-induced obesity to see if Lac-Phe was capable of helping the mice lose weight. Without modifying the mice’s movement or energy expenditure, administering Lac-Phe was associated with reduced cumulative food intake and reduced body weight from the loss of body fat, while also improving glucose tolerance over the course of ten days. The research group also found mice that lacked an enzyme called CNDP2 did not lose as much weight on an exercise regimen as mice with the enzyme, as CNDP2 is important in the production of Lac-Phe. Xu told Medical Xpress that the team plans to continue researching the molecule and investigating how it mediates its effects on the body and the brain. The ultimate goal for the group is to modulate the exercise pathway for therapeutic interventions. The team envisions a future therapeutic being able to benefit individuals who suffer from conditions that make exercise more difficult and harder to achieve, such as those with heart disease, osteoporosis and other disabilites.