Reacción a "Reactions to the identification of an exercise-secreted molecule that suppresses appetite in mice"

The positive effect of exercise in preventing and improving obesity and associated comorbidities, such as type 2 diabetes and cardiovascular disease, is well known. In recent years, intensive research has been carried out with the aim of identifying potential molecular mediators of these effects. For example, hormonal factors (myokines, mostly proteins) released by muscle during exercise that regulate metabolic and immunological changes in other tissues and that may mediate these beneficial effects. This study published in Nature identifies a metabolite produced during exercise that can reduce food intake and obesity in mice.

Jonathan Long and colleagues set out to perform a comprehensive analysis of the metabolites whose levels increase in the blood plasma of mice subjected to strenuous exercise using high-resolution biochemical methodologies (liquid chromatography-mass spectrometry, LC-MS). They found that the most significantly induced metabolite was a modified amino acid called Lac-Phe (N-lactoyl-phenylalanine), which is formed by conjugation of phenylalanine (an amino acid) with lactate (a metabolite whose production is rapidly increased by muscle undergoing strenuous exercise when there is insufficient oxygen available for aerobic cellular metabolism). 

Exercise-mediated increases in plasma Lac-Phe also occurred in other species such as horses and humans. It was found to correlate with the increase in blood lactate levels resulting from different types of exercise (higher in fast speed exercise than in aerobic endurance exercise), so the authors propose that it is a signal produced by different cell types and tissues that indicates the metabolic state during exercise, thus mediating the physiological adaptation of the organism. 

The study further explores the functional and regulatory role that Lac-Phe may play. Lac-Phe administration to mice with high-fat diet-induced obesity was shown to reduce their food intake, without affecting energy expenditure, locomotor activity or circulating levels of hormones involved in appetite regulation. In addition, chronic administration of Lac-Phe reduced body weight (due to loss of body fat) and improved glucose tolerance. However, this was not observed in mice fed a normal diet and therefore not obese).  

In loss-of-function experiments, the authors looked at mice deficient in an enzyme (CNP2) involved in Lac-Phe production and showed that mice lacking this enzyme (CNP2-KO) had higher intakes and did not lose as much weight as the control group under the same exercise regime, although no differences were observed between them in a sedentary state. Therefore, CNP2-mediated Lac-Phe production would be a process dependent on muscle lactate production during exercise.    

The results of this study are of great interest and describe a specialised and hitherto almost unknown metabolite that is produced systemically in response to strenuous intense exercise. However, where it is produced, which cells are its targets and how it exerts its anorexigenic (appetite suppressant) effects will require further characterisation. Determining how its effects are conveyed (central level effects, existence of specific receptor(s), direct effects at the cellular level, what signalling pathways are involved, concurrence/dependence/synergy with other metabolic factors or appetite regulating proteins) and what happens in humans is key to analysing future therapeutic possibilities of this molecule in terms of mimicking the benefits of physical activity for human health in muscle regeneration.