Mirabegron and Brown Adipose Tissue

Overview

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 needed. 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.