Exercise-Induced Molecule Reduces Obesity In Mice

Exercise can protect against obesity and its associated diseases, such as type 2 diabetes. But it remains unclear how exercise confers these benefits at a molecular level. Physical activity leads to many molecular changes in the body. But how it contributes to obesity prevention is not well understood.

A team of researchers led by Drs. Yong Xu at Baylor College of Medicine and Jonathan Long at Stanford University analyzed blood samples taken from mice before and after intense running on a treadmill. The scientists looked for compounds whose levels in blood plasma were higher after exercise than before. The study, which was funded in part by NIH, appeared in Nature on June 15, 2022.

The team found that the largest exercise-induced increase was in a compound called N-lactoyl-phenylalanine, or Lac-Phe. The team found a similar increase in Lac-Phe after exercise in blood samples from thoroughbred racehorses. They also analyzed blood samples from people and found increases in Lac-Phe after various types of exercise. These findings suggest that the exercise-induced increase in Lac-Phe is not unique to mice, but likely occurs across mammals.

When mice were fed a high-fat diet, injecting a large dose of Lac-Phe reduced food intake by about half over 12 hours even though blood Lac-Phe levels fell back to baseline level within an hour. Lac-Phe treatment did not affect the mice’s movement or energy expenditure. Obese mice treated with Lac-Phe daily for 10 days lost weight compared to control mice. This was due to a decrease in body fat. Obese mice treated with Lac-Phe also had lower blood glucose levels than control mice. Lac-Phe treatment, in contrast, did not affect food intake in lean mice eating a normal chow diet.

Previous research showed that an enzyme called carnosine dipeptidase 2 (CNDP2) synthesizes Lac-Phe. CNDP2 is found in many kinds of cells, including various immune cells and epithelial cells that line the surfaces of organs. The researchers confirmed that Lac-Phe production in cultured cells requires this enzyme, and that Lac-Phe is secreted from the cells. CNDP2 synthesizes Lac-Phe by combining the essential amino acid phenylalanine with lactate. Lactate is produced in the body during strenuous exercise, causing the burning sensation in tired muscles. In the cultured cells, increasing the lactate supply increased Lac-Phe production.

Mice genetically engineered to lack CNDP2 had food intake and weight gain similar to control animals on a high fat diet when sedentary. However, they ate more food and gained more weight while on a daily exercise regime. Taken together, the results imply that, as exercise raises lactate levels, CNDP2 makes more Lac-Phe, which helps regulates food intake and energy balance.

“Regular exercise has been proven to help weight maintenance, regulate appetite and improve the metabolic profile, especially for people who are overweight and obese,” Xu explains. “If we can understand the mechanism by which exercise triggers these benefits, then we are closer to helping many people improve their health.”

“Our major next step is to identify the brain Lac-Phe receptor in order to understand how Lac-Phe suppresses feeding and obesity,” Long says.