The effect of Mirabegron on brown adipose tissue in healthy young white Caucasian and South Asian men

South Asians, who are very prone to develop T2D, have less brown adipose
tissue. In South Asian individuals a disadvantageous metabolic profile,
including abdominal obesity, dyslipidemia and insulin resistance, is highly
prevalent. As a consequence, they are at higher risk for the development of
type 2 diabetes (T2D) as compared to white Caucasians and develop T2D at a
younger age and lower BMI. The underlying mechanism of this increased
predisposition for the development of T2D in South Asians is not understood,
but is likely related to their lower energy metabolism. Interestingly, using
18F-fluorodeoxyglucose (18F-FDG) PET-CT scan analysis, we have recently shown
that South Asian individuals have less brown adipose tissue (BAT) than white
Caucasians. BAT has recently been discovered as a major player in energy
metabolism in humans. In a process known as thermogenesis, BAT takes up fatty
acids (FA) and glucose from the circulation and subsequently combusts FA and
glucose into heat, thereby increasing energy expenditure and improving glucose
and fat metabolism. Of note, obese individuals have lower BAT activity as
compared to lean individuals and the activation of BAT is thus considered as a
novel therapeutic target is the treatment of obesity and T2D.
Brown adipose tissue is activated via the ß3 adrenergic receptor: a novel
therapeutic strategy? BAT is strongly innervated by the sympathetic nervous
system and the most potent stimulator is cold exposure, resulting in release of
noradrenalin (NA) from sympathetic nerve endings, which binds to *3-adrenergic
receptors on BAT thereby enhancing thermogenesis. In fact, cold acclimatisation
increases BAT volume, nonshivering thermogenesis, glucose uptake by BAT, and
decreases fat mass in healthy young men. Prolonged cold exposure, however, is
not the most suitable treatment option. ß3-receptor agonists can be used to
mimic sympathetic innervation of BAT. Our recent studies using mice with a
human-like lipoprotein profile showed that treatment with a ß3-receptor agonist
decreased fat mass, improved dyslipidemia, increased insulin sensitivity and
even attenuated the development of atherosclerosis. Likewise, *3-receptor
agonism has recently been shown to activate BAT in healthy young men as
effectively as cold exposure. Therefore, ß3-receptor agonism would be a
promising treatment option to activate BAT and enhance energy expenditure,
especially for South Asians.

The aim of the proposed study is to investigate the effect of a *3-receptor
agonist on BAT activity (MRI analysis) and energy expenditure (indirect
calorimetry), in South Asian as compared to white Caucasian individuals.

A randomised cross-over study consisting of three different regimes. They will
receive 200 mg of a *3-receptor agonist (Mirabegron), 200 mg placebo and cold
exposure (based on an individualized cooling protocol) in random order. In
between the different regimes there is a wash-out period. 230 minutes after the
intervention (i.e., administration of the compound, the placebo or cold
exposure), BAT activity will be measured using MRI (TG content). Effects on
resting energy expenditure (REE) will be monitored via indirect calorimetry
with a ventilated hood system. Furthermore, plasma glucose, lipid and
catecholamine concentrations will be monitored.

Occassion 1: Mild cold exposure for a duration of 2 hours.
Occassion 2 and 3: Administration of one dose of Mirabegron (200 mg) and one
dose of placebo in random order.

There is a risk of getting a heamatoma on after placing the intravenous cannula.
The most reported side effects of Mirabegron are increased heart rate and
nausea. During the first 3 hours after administation of the compound we will
frequently monitor heartrate and blood pressure using the finapres nova.