Topical application of the cold-mimetic L-menthol decreases wheel running without affecting the beneficial effects of voluntary exercise in mice

Topical application of L-menthol, a pharmacological cold-mimetic and agonist of the cold-sensing receptor TRPM8 (Transient Receptor Potential Cation Channel Subfamily M Member 8), has been shown to stimulate brown adipose tissue (BAT) thermogenesis and reduce weight gain in both obese and lean male mice, without affecting energy intake. While these findings suggest that L-menthol could offer a novel approach to prevent weight gain, its potential to enhance the benefits of exercise on whole-body metabolic health remains unexplored. In this study, we investigated whether daily topical L-menthol application, combined with voluntary wheel running, could enhance exercise-induced improvements in metabolic health in male and female C57BL/6J mice housed at thermoneutrality (29{degrees}C). Our results demonstrated that although L-menthol treatment reduced voluntary wheel running distance there was still a main effect of exercise to reduce fat mass, weight gain and improve glucose tolerance. Indirect calorimetry revealed that L-menthol increased total energy expenditure, potentially explaining improvements in metabolic health despite reductions in voluntary wheel running. These findings suggest that although L-menthol does not enhance the effects of voluntary exercise, it remains a promising strategy for improving metabolic health. Key pointsO_LIL-menthol treatments led to a reduction in voluntary wheel running distance C_LIO_LIDespite the reduced voluntary exercise with L-menthol, wheel running led to significant reductions in fat mass as well as improved glucose tolerance C_LIO_LITreatment with L-menthol increased energy expenditure perhaps providing an explanation for exercise-induced improvements in indices of metabolic health despite reduction in wheel running C_LI