July 12, 2022
- Researchers have found that a molecule produced during exercise by various mammals, including humans, can reduce food intake and obesity in mice.
- The results deepen our understanding of the influence of exercise on body weight.
Exercise may protect against obesity and its associated diseases, such as type 2 diabetes. But how exercise confers these benefits at the molecular level remains unclear. Physical activity causes many molecular changes in the body. But how it helps prevent obesity is not well understood.
A team of researchers led by Drs. Yong Xu of Baylor College of Medicine and Jonathan Long of Stanford University analyzed blood samples taken from mice before and after intense running on a treadmill. The scientists looked for compounds that had higher blood plasma levels after exercise than before. The study, funded in part by the NIH, appeared in Nature June 15, 2022.
The team found that the biggest exercise-induced increase was in a compound called NOT-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 results suggest that the exercise-induced increase in Lac-Phe is not unique to mice, but likely occurs in mammals.
When mice were given a high-fat diet, injection of a high dose of Lac-Phe reduced food intake by about half in 12 hours, even though blood levels of Lac-Phe fell back to baseline. within one hour. The Lac-Phe treatment did not affect the mice’s movement or energy expenditure. Obese mice treated daily with Lac-Phe 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, on the other hand, did not affect food intake in lean mice on a normal diet.
Previous research has shown that an enzyme called carnosine dipeptidase 2 (CNDP2) synthesizes Lac-Phe. CNDP2 is found in many cell types, including various immune cells and epithelial cells that line the surfaces of organs. The researchers confirmed that the production of Lac-Phe in cultured cells requires this enzyme and that Lac-Phe is secreted by the cells. CNDP2 synthesizes Lac-Phe by combining the essential amino acid phenylalanine with lactate. Lactate is produced in the body during intense exercise, causing a burning sensation in tired muscles. In cultured cells, increasing lactate intake increased Lac-Phe production.
Mice genetically engineered to lack CNDP2 had similar food intake and weight gain to control animals fed a high-fat diet when sedentary. However, they ate more food and gained more weight during a daily exercise regimen. Taken together, the results imply that as exercise increases lactate levels, CNDP2 produces more Lac-Phe, which helps regulate food intake and energy balance.
“Regular exercise has been shown to help maintain weight, regulate appetite and improve metabolic profile, especially for overweight and obese people,” Xu says. “If we can understand the mechanism by which exercise triggers these benefits, then we are one step closer to helping many people improve their health.”
“Our next major step is to identify the brain Lac-Phe receptor to understand how Lac-Phe suppresses diet and obesity,” Long said.
—by Brian Doctrow, Ph.D.
References: An exercise-inducible metabolite that suppresses diet and obesity. Li VL, He Y, Counterpois K, Liu H, Kim JT, Wiggenhorn AL, Tanzo JT, Tung AS, Lyu X, Zushin PH, Jansen RS, Michael B, Loh KY, Yang AC, Carl CS, Voldstedlund CT, Wei W , Terrell SM, Moeller BC, Arthur RM, Wallis GA, van de Wetering K, Stahl A, Kiens B, Richter EA, Banik SM, Snyder MP, Xu Y, Long JZ. Nature. Jun 2022;606(7915):785-790. doi: 10.1038/s41586-022-04828-5. Published online June 15, 2022. PMID: 35705806.
Funding: NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of General Medical Sciences (NIGMS), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Ono Pharma Foundation; BASF; United States Department of Agriculture (USDA); American Heart Association; Novo Nordisk Foundation; PXE International.