Is lactate an exercise-replacement food-derived factor? Investigation from stimulation of TGFβ2 secretion and induction of beige adipocyte formation

Background and objective: Lactate has long been considered a waste product of anaerobic metabolism. However, recent studies indicate that lactate is an important signaling molecule that regulates various metabolic processes in the body. Furthermore, the exercise-induced production of lactate is reported to stimulate the secretion of transforming growth factor-beta 2 (TGFβ2) from white adipose tissue (WAT), leading to the suppression of body fat accumulation [1]. In addition, we recently demonstrated that the intake of an amino acid mixture combined with exercise synergistically induced beige adipocyte formation in inguinal WAT (iWAT), which was associated with a significant elevation of plasma lactate levels [2]. According to these findings, we hypothesized that the oral intake of lactate would provide various exercise-related benefits in the absence of exercise. Therefore, the aim of this study was to examine whether lactate intake stimulates TGFβ2 secretion and beige adipocyte formation. Methods: Five-week-old male C57BL/6J mice were allowed to ingest sterilized water or 100 mM sodium L-lactate solution ad libitum. After 4 weeks, plasma and WAT were collected. C3H10T1/2 cells were differentiated into beige adipocytes and then treated with lactate and/or N-acetylcycteine (NAC). After treatment, reactive oxygen species (ROS) production and uncoupling protein 1 (UCP1) mRNA levels were determined. Results: Lactate intake did not significantly increase plasma TGFβ2 levels, despite the increase in plasma lactate levels. However, lactate significantly induced beige adipocyte formation in iWAT. Lactate significantly induced the expression of the lactate transporter MCT1 and lactate dehydrogenase B (LDHB). These data suggest that lactate incorporated via MCT1 is metabolized into pyruvate by LDHB, which would increase the NADH:H+/NAD+ ratio and ROS production. Lactate treatment significantly induced ROS production and UCP1 expression in differentiated C3H10T1/2 cells, which were significantly suppressed by treatment with NAC. Conclusions: Lactate intake induces beige adipocyte formation. ROS function as a second messenger of lactate and are involved in the induction of beige adipocyte formation. Lactate may be used as an exercise-replacement food-derived factor.