NCT07030725

Menthol Stimulation of Brown Adipose Tissue in Humans: Aim 1

Targeted TRPM8 Stimulation and Brown Adipose Tissue Activation in Humans

• Status: Recruiting
• Phase: EARLY_Phase 1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Sponsor: Indiana University · Academic / Other
• Sex: All
• Age: 18 Years – 40 Years
• Healthy volunteers: Accepted

Summary

Brown adipose tissue becomes activated during cold conditions to increase thermogenesis (i.e., energy expenditure). Topical menthol application increases resting energy expenditure but it is unclear whether brown adipose tissue activation contributes to this rise in the energy expenditure. The overall goal with this project is to determine whether topical menthol application stimulates brown adipose tissue.

Detailed description

Brown adipose tissue (BAT) is an important organ in the regulation of energy balance, particularly in small mammals and infants. Until recently, BAT was thought to be nonexistent and thus metabolically irrelevant in adult humans, primarily due to the lack of methods capable of localizing and measuring its metabolic contribution. Since its discovery in adult humans, various reports have shown that BAT can be activated in response to cold exposure to increase non-shivering thermogenesis (NST). NST results primarily from the expression of uncoupling protein 1 (UCP1) in BAT, dissipating the energy of the proton motive force as heat, thus uncoupling it from mitochondrial respiration. Notably, activation of BAT augments glucose uptake, improving glucose regulation and insulin sensitivity. Whereas mild cold exposure and beta-3-adrenergic pharmacological stimulation have previously been used to augment BAT-induced thermogenesis, recent investigations have proposed novel methods for UCP1 expression. Menthol, a chemical cooling agent naturally produced from mint oils, elicits a cold sensation when topically applied to the skin and is used clinically as a pain analgesic. This sensation is derived from the activation of cold-sensitive receptors known as transient receptor potential melastatin 8 (TRPM8), a primary sensor of thermal stimuli in the peripheral nervous system. While TRPM8 is predominately located on the cell membrane of sensory neurons, its expression has been recently detected on BAT, highlighting a potential alternative avenue for stimulating this highly thermogenic tissue. Previous reports have alluded to menthol's potential as a vehicle for BAT activation. Vizin et. al observed a persistent increase in energy expenditure following a short-term topical menthol intervention in a rodent model. Moreover, Valente et. al observed an increase in metabolic rate in humans following a single administration of menthol to the skin surface of the neck and of the right arm and leg. While both groups attribute their findings to menthol-induced BAT activation, there were no markers of BAT activation utilized in their investigations. Therefore, there is a significant scientific gap in the understanding of menthol-induced thermogenesis. Despite the promising thermogenic potential of topical menthol application, the previously reported increase in metabolic rate may be attributed to other forms of thermogenesis, such as shivering thermogenesis and NST in skeletal muscle. Furthermore, methodological differences regarding application site/area, dosage of menthol, evaporative potential of the skin, and resting vasomotor tone complicate most studies in this field, providing limited clarity on the link between TRPM8 stimulation and UCP1-dependent NST. Due to this, proper characterization of menthol's influence, specifically on physiological responses that contribute to human thermoregulation, is warranted. Specific Aim: Determine the specific thermogenic mechanism(s) underlying the increase in energy expenditure evoked by menthol induced TRPM8 activation. Hypothesis: Topical menthol application to the anterior aspect of the thorax will increase thermogenesis (i.e., resting energy expenditure) via activation of BAT (i.e., supraclavicular skin temperature; indirect-noninvasive measure of BAT activity) and augmentation of skeletal muscle blood flow (i.e., estimated via changes in limb blood flow) versus application of a sham cream.

Conditions

• Regulation of Energy Expenditure

Interventions

Type	Name	Description
DRUG	Menthol Gel	Menthol (5% L-menthol) will be applied to the anterior thorax.
DRUG	Sham	Sham gel applied to the anterior thorax.
BEHAVIORAL	Time control	No gel applied to anterior thorax.

Timeline

• Start date: 2025-03-27
• Primary completion: 2026-03-01
• Completion: 2026-09-01
• First posted: 2025-06-22
• Last updated: 2025-06-25

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study