TRPM8 Stimulation, in the Absence of Cold, Increases Energy Expenditure and Activates Supraclavicular Brown Adipose Tissue in Humans

Background: In humans, cutaneous cold sensing is mediated by transient receptor melastatin 8 (TRPM8). TRPM8 activation via cold-mimetic compounds (i.e., topical menthol), evokes thermo-effector responses and has been suggested to stimulate brown adipose tissue (BAT) activity in rodents. However, the thermogenic responses evoked by targeted cutaneous TRPM8 activation in humans remain unclear. Thus, we tested the hypothesis that a single application of topical menthol to the anterior aspect of the thorax would increase thermogenesis and elevate supraclavicular BAT activation (i.e., supraclavicular skin temperature; Tsc) versus sham (SHAM) and time control (CON) visits. Methods: 12 healthy adults (age: 23±2 y; body fat: 21±4%, 6 women) participated in the study. Participants completed three single-blind randomized visits: menthol, SHAM, and CON. At the start of each visit, participants entered a whole-body indirect room calorimeter (28°C, 50% RH) and rested for 30 min prior to baseline measurements. Participants then self-applied 0.1 ml/cm2 of either a SHAM cream (a water-soluble lubricating jelly) or a 5% menthol cream to the anterior thorax (16.5% of total body surface area). No cream was applied during the CON visit. During the 2 h measuring period, the rate of energy expenditure (REE; kcal/min), O 2 consumption (VO 2 ; ml/kg/min), CO 2 production (VCO 2 ; ml/kg/min), and respiratory exchange ratio (RER) mean values were calculated for the last 5 min of each 15 min. Cumulative energy expenditure (EE; kcal) was determined using the abbreviated Weir formula. BAT activity was assessed via infrared thermography of Tsc and expressed relative to sternal skin temperature. Mean skin temperature (12 sites) and rectal temperature were measured and used to calculate mean body temperature (Tb). Shivering was assessed via electromyography (EMG; thigh, chest, and biceps). Forearm skin blood flow, estimated by red blood cell flux, was assessed via integrated laser Doppler. Data were analyzed in 15 min intervals and reported as mean ± SD. Results: There was a main effect of condition for REE (P=0.04), which was higher in menthol (1.24±0.20 kcal/min) vs. SHAM (1.18±0.21 kcal/min; P=0.01) and CON (1.19±0.22 kcal/min; P< 0.05). There was a main effect of condition for VO 2 (P=0.05), which was higher in menthol (5.15±0.71 ml/kg/min) vs. SHAM (4.93±0.65 ml/kg/min; P< 0.05) and CON (4.95 ± 0.56 ml/kg/min; P< 0.05). No main effects were observed for VCO 2 (P=0.10) and RER (P=0.71). EE was greatest in menthol (148±28 kcal) vs. SHAM (141±28 kcal; P< 0.05) and CON (141±29 kcal; P=0.01). A condition x time interaction was observed for relative Tsc, which was greater in menthol (1.93±0.26°C) vs. SHAM (1.63±0.09°C; P=0.03), but not CON (1.75±0.07°C; P=0.25). A condition x time interaction was observed for Tb, which was greater in menthol (35.65±0.10°C) vs. SHAM (35.48±0.03°C; P< 0.05) but not CON (35.62±0.03°C; P=0.42). No main effects were observed for EMG (P=0.22) or red blood cell flux (P=0.32). Conclusion: Topical menthol applied to the anterior thorax increased energy expenditure and elevated supraclavicular skin temperature, an indicator of brown adipose tissue activation, versus SHAM conditions. These effects occurred without changes in shivering or peripheral skin blood flow, suggesting that TRPM8 stimulation can enhance thermogenesis independent of cold exposure. Collectively, these findings provide the first evidence in humans that targeted TRPM8 stimulation can increase metabolic heat production and may represent a non-thermal strategy for stimulating supraclavicular BAT activity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.