Menthol to Induce Non-shivering Thermogenesis via TRPM8/PKA Signaling for Treatment of Obesity

Abstract

Increasing basal energy expenditure via uncoupling protein 1 (UCP1)-dependent non-shivering thermogenesis is an attractive therapeutic strategy for treatment of obesity. Transient receptor potential melastatin 8 (TRPM8) channel activation by cold and cold mimetics induces UCP1 transcription and prevents obesity in animals, but the clinical relevance of this relationship remains incompletely understood. A review of TRPM8 channel agonism for treatment of obesity focusing on menthol was undertaken. Adipocyte TRPM8 activation results in Ca 2+ influx and protein kinase A (PKA) activation, which induces mitochondrial elongation, mitochondrial localization to lipid droplets, lipolysis, β-oxidation, and UCP1 expression. Ca 2+ -induced mitochondrial reactive oxygen species activate UCP1. In animals, TRPM8 agonism increases basal metabolic rate, non-shivering thermogenesis, oxygen consumption, exercise endurance, and fatty acid oxidation and decreases abdominal fat percentage. Menthol prevents high-fat diet-induced obesity, glucose intolerance, insulin resistance, and liver triacylglycerol accumulation. Hypothalamic TRPM8 activation releases glucagon, which activates PKA and promotes catabolism. TRPM8 polymorphisms are associated with obesity. In humans, oral menthol and other TRPM8 agonists have little effect. However, topical menthol appears to increase core body temperature and metabolic rate. A randomized clinical control trial of topical menthol in obese patients is warranted.

Involvement of TRP Channels in Adipocyte Thermogenesis: An Update

“…The mRNA and protein expression levels of TRPM8 are significantly increased in the differentiated adipocytes, suggesting the importance of TRPM8 for adipocyte thermogenesis ( Rossato et al, 2014 ). In cultured adipocytes, menthol induced an up-regulation of UCP1 expression which may through a protein kinase A pathway, which subsequently increases BAT thermogenesis and WAT “browning” ( Ma et al, 2012 ; Jiang et al, 2017 ; Sanders et al, 2020 ). Besides, it has been reported that cold-sensing TRPM8 channel participates in the regulation of clock and clock-controlled genes in BAT thermogenesis ( Moraes et al, 2017 ).…”

Nutraceuticals in Brown Adipose Tissue Activation

“…In addition, menthol represents a ligand for the TRP melastatin 8 (TRPM8) channel, a TRP family member whose activation increses UCP1 expression in adipocyte cultures. Such effects of menthol were observed also in the adipose tissue of mice [ 62 ]. Expression of TRPM8 in brown adipocytes suggests that TRPM8 ligands can directly activate BAT.…”

Cold stimuli, hot topic: An updated review on the biological activity of menthol in relation to inflammation

“…This adds a complication to the observed effects of menthol, as the antioxidant activity may have driven much of the improvements seen in terms of the histopathology of lesions or the clinical status of affected animals. While this does not preclude the specific effects of menthol on the inflammatory response, it may highlight an adjunctive or indirect mechanism through which this anti-inflammatory activity occurs, via the reduction of reactive oxygen species or antioxidant activity ( 53 ). Separation of these pathways and further elucidation of menthol’s effects on inflammatory pathways alone may be valuable in future research.…”