Glucose Metabolism in Brown Adipose Tissue (BAT) in Young Healthy Men Evaluated by Deuterium Metabolic Imaging (DMI)

The prevalence of obesity and type 2 diabetes has increased exponentially over the past decades giving rise to substantial individual as well as health economic costs. Therefore, more research are warranted in the development of new prevention and treatment strategies.

In 2009 findings using 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (FDG-PET) verified the presence of metabolically active brown adipose tissue (BAT) in adult humans and since then BAT has been revitalized as a potential target organ in the treatment of obesity and metabolic syndrome. Through increased activity of the sympathetic nervous system (SNS) and the corresponding release of norepinephrine (NE), cold is among the most potent physiological activators of BAT, but other stimulating factors such as natriuretic peptides, BMP8b, COX2, bile acids, thyroid hormones, FGF21 and even bioactive food components are known. Activated BAT increases the energy expenditure via uncoupling (via uncoupling protein 1 - UCP1) of the inner mitochondrial membrane resulting in leak of electrons and heat production at the expense of ATP production (non-shivering thermogenesis) a mechanism evolutionary developed to sustain body temperature. It is known that age, gender, degree of obesity and insulin resistance is associated with BAT activity. Furthermore, activated BAT generally improves glucose tolerance, insulin sensitivity and promotes weight loss in rodent models giving rise to hopes for similar effects in humans. However, deeper insight into in vivo BAT metabolism in humans are still warranted. BAT is anatomically located along the major vessels, surrounding the large organs, the anterior neck, sub-clavicular, axillary and in the inguinal fossa. In this proposed clinical study, the investigators wish to examine the anterior neck and supraclavicular area that are known to comprise the largest BAT depots.

When BAT is activated glucose- as well as free fatty acids uptake are greatly increased compared to non-activated BAT and therefore the most widely used method for in vivo assessment of BAT activity and imaging in humans is currently FDG PET/CT. This well-known imaging modality relies on the radioactive glucose tracer 18FDG to detect tissues with high glucose consumption e.g. activated BAT. The 18FDG signal gives an indication of the distribution of glucose uptake and phosphorylation in the tissue. However, FDG PET imaging does neither provide information on spatial metabolic activity, nor the different metabolites downstream from glucose as FDG is not further metabolized when taken up in the tissue. Moreover, due to the radiation-exposure associated with FDG PET/CT repetitive studies of BAT in healthy subjects are limited.

New in vivo methods (preferably non-invasive) are warranted in order to reveal the true potential of targeting BAT thermogenesis to prevent and/or treat cardio metabolic disorder.

To accommodate this need, Deuterium Metabolic Imaging (DMI) may be a potential tool. DMI is a novel non-radioactive, non-invasive method that allows for spatial as well as metabolic imaging after oral administration of [6,6'- H ]-glucose. Deuterium is a stable isotope of hydrogen that can be bound to different metabolites, in this case glucose. This method allows for metabolic imaging and production of 2H MR spectra of metabolites downstream from glucose uptake that can be quantified. The method has already been applied in studies of the human and rat brain using spectroscopic imaging at 4T and 11.7T respectively, but has never been used to assess glucose metabolism in human BAT.