Bioavailable Menthol (Transient Receptor Potential Melastatin-8 Agonist) Induces Energy Expending Phenotype in Differentiating Adipocytes

Abstract

Recent evidence supports the role of menthol, a TRPM8 agonist, in enhanced energy expenditure, thermogenesis and BAT-like activity in classical WAT depots in a TRPM8 dependent and independent manner. The present study was designed to analyse whether oral and topical administration of menthol is bioavailable at subcutaneous adipose tissue and is sufficient to directlyinduce desired energy expenditure effects. GC-FID was performed to study menthol bioavailability in serum and subcutaneous white adipose tissue following oral and topical administration. Further, 3T3L1 adipocytes were treated with bioavailable menthol doses and different parameters (lipid accumulation, “browning/brite” and energy expenditure gene expression, metal analysis, mitochondrial complex’s gene expression) were studied. No difference was observed in serum levels but significant difference was seen in the menthol concentration on subcutaneous adipose tissues after oral and topical application. Menthol administration at bioavailable doses significantly increased “browning/brite” and energy expenditure phenotype, enhanced mitochondrial activity related gene expression, increased metal concentration during adipogenesis but did not alter the lipid accumulation as well as acute experiments were performed with lower dose of menthol on mature adipocytes In conclusion, the present study provides evidence that bioavailable menthol after single oral and topical administration is sufficient to induce “brite” phenotype in subcutaneous adipose tissue However, critical dose characterization for its clinical utility is required.

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

“…1). 21,22,29,39,48 The pleiotropic effects of PKA activation in this context, however, warrant further mechanistic discussion to glean additional therapeutic insights.…”

“…62 cAMP activates protein kinase A (PKA) to induce uncoupling protein 1 (UCP1) transcription. 2,[20][21][22]26,30,33 Once translated, UCP1 proteins are imported into mitochondria and localized to the inner mitochondrial membrane, where they allow protons to diffuse down an electrochemical gradient into the mitochondrial matrix, dissipating the energy of the proton motive force as heat instead of generating adenosine triphosphate. 1 PKA also phosphorylates and thereby activates dynamin-related protein 1 (Drp1), which induces mitochondrial fusion and elongation around lipid droplets.…”

“…tumor necrosis factor receptor superfamily member 9, and Homeobox C10. 22 Menthol was more effective at increasing UCP1 expression and uncoupled respiration in white adipocytes than in brown adipocytes. 39 In white adipocytes, menthol and icilin significantly increased UCP1 mRNA and protein levels, thermogenesis, glucose uptake, mitochondrial membrane potential, and mitochondrial elongation and clustering around lipid droplets independent of genes involved in mitochondrial biogenesis through TRPM8 activation and consequent Ca 2+ influx.…”

miRNAs and Novel Food Compounds Related to the Browning Process

“…However, to date, no studies have been found that directly relate this species to miRNA and the browning process. Nevertheless, an in vitro study showed that L-menthol administration at bioavailable doses significantly increased browning/brite and the energy expenditure phenotype and enhanced mitochondrial activity-related gene expression [163]. In addition, an in vivo experiment has found that dietary menthol enhanced WAT browning and improved glucose metabolism in HFD-induced obesity mice, which suggests that TRPM8 might be involved in WAT browning by increasing the expression levels of genes related to thermogenesis and energy metabolism [164].…”

Transient Receptor Potential (TRP) Channels in Health and Disease

“…Soon after cloning the eighth member— TRPM8 —of the melastatin family of TRP channels, several laboratories have reported that natural and synthetic cooling mimetics, such as icilin, eucalyptol, and menthol, activate this channel (reviewed in [22]). Dr. Khare and colleagues now provide evidence that the application of menthol may induce a so-called “browning” effect in subcutaneous adipose tissue, although a direct involvement of TRPM8 has not been identified yet [23].…”