Obesity has become a global epidemic, with more than two-thirds of adults worldwide classified as overweight/obese [1]. Lifestyle modifications to combat obesity, such as exercise and caloric restriction, have shown some efficacy against obesity in the short term; however, obesity is becoming increasingly prevalent [1,2]. Therefore, alternative and novel approaches to effective weight loss are urgently needed.

A very recent metabolomics study performed using animal models of exercise has showed that exercise induced the biosynthesis of N-lactoyl-phenylalanine (Lac-Phe), a circulating signalling metabolite that suppresses feeding and obesity selectively in mice fed a high-fat diet [3]. Authors found that this increase is the most notable among other metabolite changes following acute exercise [3]. The production of Lac-Phe from lactate (a metabolic by-product of exercise) and phenylalanine (an essential amino acid) occurs in CNDP2 (cytosolic nonspecific dipeptidase 2)-positive cells in which this cytosolic enzyme catalyses the synthesis through the condensation of lactate (Lac) and phenylalanine (Phe) [3], [4], [5]. In CNDP2-knocked out cells, extracellular Lac-Phe levels were reduced by more than 75% [3]. Authors showed that in diet-induced obese mice but not in lean mice, pharmacological-mediated increases in Lac-Phe reduces food intake by approximately 50% without affecting movement or energy expenditure, and that chronic administration of Lac-Phe decreases adiposity, obesity and body weight, and improves glucose homeostasis [3]. Authors noted that although Lac-Phe reduces adipose tissue weight, it does not cause any changes in the weights of other organs [3]. They also showed that lactate or phenylalanine alone does not produce any of the observed changes, which clearly shows that the intact peptide conjugate is required for its physiological contribution to the anti-obesity effects of exercise [3].

Trans-10, cis-12 conjugated linoleic acid (t10,c12-CLA) is a conjugated dienoic isomer of linoleic acid and a naturally occurring dietary trans fatty acid found in food from ruminant sources [6- 9]. t10,c12-CLA induces weight and body fat loss by adipose tissue fatty acid oxidation (FAO), energy expenditure and adipose apoptosis (reduced adiposity) in animal models and humans; therefore, it has been promoted as an anti-obesity agent [10], [11], [12].However, the mechanisms of weight reduction by t10,c12-CLA are not completely understood [13, 14].

Since CNDP2 promotes the production of Lac-Phe which decreases adiposity, obesity and body weight, and t10,c12-CLA and caloric restriction shows similar anti-obesity effects, we hypothesized that t10,c12-CLA and caloric restriction might lead to increased CNDP2 expression in certain tissues, thereby contributing to Lac-Phe-mediated changes in the suppression of feeding and obesity, at least to a certain extent. Indeed, by using publicly available gene expression datasets, we found that t10,c12-CLA increases CNDP2 expression in adipose tissue in mice, and its effect on CNDP2 expression is higher than that of linoleic acid in mouse adipocytes. Caloric restricted diet similarly increased CNDP2 expression in white adipose tissue in rats, but not in heart tissue, in parallel to the observation that Lac-Phe reduces only adipose tissue weight among other organs, highlighting the presence of tissue-specific effects [3]. Lastly, we found that, aging decreases CNDP2 expression in white adipose tissue in rats, possibly leading to decreased Lac-Phe levels and increased predisposition to obesity; however, further research is required to confirm these inferences.