In the current study, the effect of one single dose of Mirabegron (200 mg) versus placebo and cold-exposure will be studied in health young (18-30 years) Dutch South Asian (n=10) and Dutch Caucasian (n=10) men.
All study subjects will be screened. If the subject meets all the inclusion criteria, is willing to participate in the study and has signed the informed consent, he will be included. All subjects will be asked not to make any changes in their usual diets and physical activities before the start of the whole study.
At screening a thorough medical history and physical examination will be performed. Subjects will be examined while in the fasting state. Anthropometric measurements will be performed as well as a BIA measurement for determination of body fat percentage and basal blood sample will be taken by means of a venapunction. Basal blood measurements include kidney, liver, thyroid, hemoglobulin, natrium, kalium, ureum and lipid parameters as well as glucose concentrations.
If subjects are eligible to participate they first will complete Study day 1, on which we will measure BAT activity and volume before and after cold exposure. Subject will undergo a baseline oxycon and finapres measurement to determine REE and blood pressure and heart rate (30 min). After this a baseline MRI scan will be made followed by an individualized cooling protocol so that the maximum non-shivering thermogenesis is reached. During the cold exposure, skin temperature will be measured via 'iButtons'. One iButtons will be placed under the armpit as an approximation of the 'core temperature'. When shivering temperature is reached, stable cooling period will start (t=0). After 30 minutes of stable cold exposure (t=30) REE and blood pressure and heart rate will be analyzed a second time using a ventilated hood system and the finapres. Thereafter (t=60) BAT activity and volume will be measured using a second MRI scan. Furthermore, during the cooling procedure a venous blood sample will be obtained every 15 minutes to monitor dynamic changes in plasma lipids. In addition, plasma catecholamine concentrations will be determined. If there is no increased BAT activity upon cold stimulation the subject will be excluded from further participation in the study. If there is detectable BAT activity on Study day 1, subjects will participate in Study days 2 and 3 and will be randomized to receive first Mirabegron or placebo to minimize bias.
On study day 2 first baseline oxycon and finapres measurements will be performed to determine REE and blood pressure and heart rate (30 min). Thereafter, the subject will receive a single dose of 200 mg Mirabegron (four tables of 50 mg) (or placebo) (t=0). Again skin temperature will be measured via 'iButtons'. One iButton will be placed under the armpit as an approximation of the 'core temperature'. After 1, 2 and 3 hours (t=60, t=120 and t=180) REE is analyzed using a ventilated hood system and blood pressure and heart rate are monitored using the finapres. Thereafter, 3.5 hours after the administration of the compound (t=210) BAT activity and volume will be determined using an MRI scan. Furthermore, a venous blood sample will be drawn every 15 minutes to monitor changes in plasma lipids. In addition, plasma catecholamine concentrations will be determined.Study day 3 is exactly the same as study day 2, except this time the subject will receive the other compound (either 200 mg Mirabegron or placebo).
All study days will take place at the Leiden University Medical Centre (LUMC). Between study days 2 and 3 a wash-out period of 13 days will be maintained to make sure that the drug is out of the body during the next exam.
