Obesity and type 2 diabetes (T2D) are emerging problems worldwide. In particular South Asian
individuals (representing 20% of the world population) have an increased risk of obesity and
related disorders. They are at higher risk for the development of T2D as compared to white
Caucasians and develop T2D at a younger age and with lower BMI. The underlying mechanisms
that might explain these ethnical differences have not been clarified or understood yet. As a
consequence, treatment options are limited and unfocussed, and novel specific strategies are
Brown adipose tissue (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 FA metabolism. Using
18F-fluorodeoxyglucose (18F-FDG) (positron emission tomography/computed tomography) PET-CT
scan analysis investigators have recently shown that South Asian individuals have less brown
adipose tissue (BAT) than white Caucasians. This might suggest that they have a lower energy
metabolism, which could underlie their increased predisposition for obesity and the
development of T2D.
Activation of BAT, for example by cold exposure, was shown to have beneficial metabolic
effects in humans. Cold acclimatization can increase BAT volume, nonshivering thermogenesis,
glucose uptake by BAT, as well as decrease fat mass in healthy young men. Therefore
activation of BAT is considered as a novel therapeutic target in the treatment of obesity and
T2D. As cold exposure is not the most desired therapeutic strategy for humans, current
pre-clinical research focuses on pharmacological activation of BAT.
β3-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 β3-receptor
agonist decreased fat mass, improved dyslipidemia, increased insulin sensitivity and even
attenuated the development of atherosclerosis. Likewise, the novel β3-receptor agonist
(Mirabegron) 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.
Currently the most common way to visualize BAT in humans is by 18F-FDG PET-CT scan. However
this method is both expensive and invasive, as it uses ionizing radiation. Recently, MRI,
which has no radiation burden, has emerged as a novel method to visualize BAT in humans.
Activation of BAT results in combustion of intracellular lipid stores, which eventually leads
to a lower triglyceride (TG) content. MRI can measure TG content of tissue, and using MRI
technology the activation of BAT can be quantified by the relative reduction in the TG
content of BAT. The use of MRI to visualize and quantify BAT activity is a safe,
cost-effective and innovative alternative to PET-CT, which has a potential to become a new
gold standard in the nearby future.
To investigate whether β3-receptor agonism has therapeutic potential to improve the metabolic
phenotype of South Asians, investigators will perform a randomized cross-over study in which
20 healthy young men aged 18-30 years with a lean body type (BMI <25 kg/m2) are included.
Dutch South Asian individuals (n=10) and matched Dutch white Caucasian individuals (n=10)
will participate in a cross-over study consisting of three different regimes.
This study will investigate whether β3-receptor agonism has therapeutic potential to improve
the metabolic phenotype of South Asians. The effects of a β3-receptor agonist on BAT activity
in South Asians have never been studied before. Elucidating the effects of this β3-receptor
agonist on BAT activity in South Asians might have major clinical implications, as it might
result in the discovery of a potential novel treatment strategy to combat obesity and T2D in
this especially vulnerable population.