Vigorous exercise decreases appetite and promotes weight loss through the production of the metabolite Lac-Phe

Exercise is highly effective in protecting against obesity and related cardiometabolic diseases, including type 2 diabetes. However, the cellular and molecular mechanisms by which exercise exerts beneficial effects on metabolism are not yet well known. A team of researchers recently investigated the issue using a metabolomics approach, i.e. by studying the expression of all the metabolites following vigorous exercise sessions (running). The metabolite that increased the most in response to exercise in mice was N-lactoyl-phenylalanine (Lac-Phe), a result that was later confirmed in thoroughbred racehorses.

Lac-Phe: An already known metabolite
The metabolite N-lactoyl-phenylalanine was first identified a decade ago, but until recently its function was unknown. Lac-Phe is produced from lactate, which is generated in muscle cells during vigorous exercise and then released into the bloodstream, and the amino acid phenylalanine (see figure below). The formation of this metabolite is catalyzed (i.e., greatly accelerated) by the CNDP2 enzyme, which is expressed in several cell types (e.g., immune system cells, epithelial cells). Without knowing its exact function, we already knew that this metabolite increases in the blood of people who have exercised.

Figure 1. Lac-Phe formation catalyzed by the CNDP2 enzyme.

Lac-Phe decreases appetite and body weight
The activity of Lac-Phe was tested in obese mice (fed a high-fat diet). Daily administration of Lac-Phe caused obese mice to lose 7% of their body mass after 10 days, reduced adiposity, and improved blood sugar control. The activity level of the mice remained normal, but they simply ate less food (–50% over a 12-h period). Curiously, the administration of Lac-Phe to lean mice had no effect on their appetite. The researchers hypothesized (unconfirmed) that this difference could be due to a greater permeability of the blood-brain barrier in obese mice, which would result in higher concentrations of Lac-Phe in the brains of these mice, compared to lean mice.

In order to demonstrate the contribution of the Lac-Phe metabolite to the anti-obesity effect of exercise, the researchers used CNDP2-KO mice that are genetically modified to produce less Lac-Phe (by removal of the Cndp2 gene). CNDP2-KO mice and normal mice were fed a high-fat diet and subjected to a regular exercise protocol for 40 days. CNDP2-KO mice ate more food and gained 13% more weight (after 40 days) than normal mice. These results clearly show that Lac-Phe is involved in appetite control in mice.

And in humans?
The researchers looked at Lac-Phe levels in healthy people before and after exercising in two independent cohorts. In a first cohort of 36 people, Lac-Phe was the third metabolite that increased the most after exercising. This increase in Lac-Phe persisted until at least 60 minutes after ceasing to exercise, whereas that of lactate returned to near zero after 60 minutes.

Participants in the second cohort participated in three distinct types of exercise: sprint (maximum-intensity cycling), endurance (moderate-speed cycling), and resistance (strength training). Lac-Phe levels increased after all three types of exercise (Figure 2), but much more after cycling sprints (approx. 8 times) than after resistance exercise (approx. 2.6 times) or endurance exercise (approx. 1.6 times).

Figure 2. Lac-Phe levels before and after exercise in a cohort of eight people. All participants did three different types of exercise: intense exercise (cycling sprints), endurance exercise (90 minutes of cycling at moderate speed), and resistance exercise (bilateral knee extension exercise). Lac-Phe concentration was measured in blood samples taken before and after each exercise at t=0, 60, 120 and 180 minutes. Adapted from Li et al., 2022.

It is not yet known whether Lac-Phe decreases appetite in humans as it does in mice; this remains to be demonstrated. Furthermore, does Lac-Phe act on appetite control in the brain as has been shown for ghrelin and leptin, appetite and satiety hormones? There is no doubt that future research on this subject will provide us with interesting discoveries that could have a significant impact on human health.

Researchers hope to one day be able to produce a drug based on Lac-Phe that could decrease the appetite of obese people who cannot exercise due to other health problems. However, dietary supplement enthusiasts should be aware that Lac-Phe is completely inactive when taken orally. For people who want to lose weight through exercise, it therefore seems to be beneficial to increase the intensity as much as possible in order to further reduce appetite and consequently post-workout calorie intake.