Menthol Stimulation of Brown Adipose Tissue in Humans: Aim 1

Phase

Condition

N/A

Treatment

Time control

Menthol Gel

Sham

Clinical Study ID

NCT07030725

24695

Ages 18-40
All Genders
Accepts Healthy Volunteers

Study 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.

Eligibility Criteria

Inclusion

Inclusion Criteria:

Fluency in English
Participate in 150 minutes or more of at least moderate intensity exercise per weekduring the previous year. Assessment of moderate intensity physical activity will bedetermined via the International Physical Activity Questionnaire (i.e., IPAQ) (described in detail in Section 7.0). This questionnaire defines moderate intensityexercise as "activities that take moderate physical effort and make you breathesomewhat harder than normal".
Body fat ≤ 30% as determined by DEXA scan
Be cleared for physical activity according to the 2020 Physical Activity ReadinessQuestionnnaire (PAR-Q+).

Exclusion

Exclusion Criteria:

Any autonomic cardiovascular, metabolic, neurologic, endocrine, or respiratorydisease, that, in the opinion of the investigator, would exclude them fromparticipation.
Previously diagnosed liver and/or kidney dysfunction, including, but not limited to,acute and/or chronic kidney disease, cirrhosis, hepatitis, and fatty liver disease.
Women who are pregnant or breastfeeding.
Current use of tobacco or electronic cigarette, or regular (i.e., more than twice aweek) use within the last 1 year.
History of peripheral cold injury, skin disorder (eczema, psoriasis), or excessivetattooing.
Known chronic (i.e., cancer, surgery) or acute conditions (i.e., diarrhea,constipation) of the rectum.
Menthol allergy (described in detail in Section 7.0 and 9.0). Menthol can cause skinirritation when applied topically, especially for people with sensitive skin orallergies. For this reason, recruited participants will be screened for a mentholallergy during the informed consent/screening visit. We will apply a small quantityof the cream (~2ml) to an isolated body area to limit skin exposure. In the case arash develops during the application of the cream, research staff will irrigate thearea to remove the substance and limit further exposure. A 24-hour follow-up phonecall initiated by research staff will be implemented to follow-up on all adversereactions. Detectable BAT activation during a localized cold stress test (i.e., facecooling test) (procedure described in detail in Section 7.0).
Using medications with direct effects on the cardiovascular system including, butnot limited to:
Anticoagulants.
Antiplatelet agents.
ACE Inhibitors.
Angiotensin II receptor blockers.
Angiotensin-receptor neprilysin inhibitors.
Beta blockers.
Calcium, potassium, or sodium channel blockers.
Cholesterol lowering medications.
Digitalis preparations.
Diuretics.
Vasodilators.
Anticholinergics.

Study Design

Time control

March 27, 2025

September 30, 2026

Study 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.

Connect with a study center

Indiana University
Bloomington, Indiana 47405
United States
Active - Recruiting

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