The purpose of the study is to asses brown adipose tissue activity after a cold mild stimulus, preceded by 200mg caffeine or placebo administration.

Brown adipose tissue (BAT) activation is typically through beta3-adrenoceptors (beta3-AR), but beta3-alone are less efficacious than cold in activating human BAT. Recent research suggests that adenosine, released during cold exposure, plays a key role in BAT thermogenesis. This study aims to investigate the role of the adenosine A2A receptor (A2AR) in BAT activation through a randomized trial with mild cold exposure and caffeine, a potent A2AR antagonist, to explore new therapeutic strategies for metabolic diseases.

This is a randomized, double-blind, placebo-controlled cross-over trial involving healthy volunteers. The study includes a screening visit and two main study visits (A and B), which will occur in random order.

During the two study visits, resting energy expenditure will be assessed by indirect calorimetry under warm conditions and following mild cold exposure, after administration of either caffeine or placebo. For cold exposure, participants will wear cooling sleeves around the waist, which gradually lower the surface body temperature to 10°C or to the lowest tolerable temperature without inducing shivering.

Additionally, BAT activity will be assessed using 18F-FDG PET/CT, performed 30 minutes after the injection of 75 MBq of 18F-FDG.

Inclusion Criteria:

• BMI 18.5 to 25 kg/m2
• Able to give informed consent as documented by signature
• Moderate caffeine consumption (1 to 3 cups of coffee per day)
• Increase of EE in response to mild cold of ≥ 5% of REE

Exclusion Criteria:

• Known hypersensitivity or allergy to caffeine
• Concomitant medication other than prescription free analgesics (paracetamol and NSAID) and oral contraceptives
• Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease, cardiac arrhythmia, hypertension, diabetes mellitus, hyper- or hypothyroidism)
• History of depressive disorder or anxiety disorder
• Smoker / habitual tobacco use
• Habitual excessive alcohol use
• Regular consumption of caffeine containing energy drinks
• Weight change of >5% within 3 months prior to inclusion
• Systolic blood pressure >140 mmHg and/or diastolic blood pressure > 95 mmHg.
• Resting heart rate >90 bpm
• Hypersensitivity to cold (e.g. Raynaud syndrome)
• Known or suspected non-compliance, drug or alcohol abuse
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant.
• Enrolment of the investigator, his/her family members, employees, and other dependent persons
• Enrolment into another study using ionizing radiation within the previous 12 months.
• Pregnancy or lactation