Regulation of brown adipose tissue activity in humans by glucocorticoids

Brown fat, also known as brown adipose tissue (BAT), is a unique tissue which functions to promote energy expenditure to raise body temperature. This type of fat has been extensively studied in small animals such as mice and is very important in these animals, as mice lacking BAT become obese. However brown fat has only recently been discovered in adult humans, and the importance of BAT and how it is controlled in humans is unclear. The current methods available to detect BAT activity in humans are inadequate, therefore this proposed project aims to build on existing tools and develop new techniques to determine the importance of BAT to energy expenditure in healthy humans. BAT biopsies will also be obtained from patients undergoing surgery and this tissue will be grown in culture dishes to investigate the important processes controlling its activation. Glucocorticoids are a type of steroid hormone which cause obesity if levels are persistently elevated. Glucocorticoids suppress energy production by brown fat in small animals, and we will use our new techniques to test whether glucocorticoids also suppress BAT activity in humans. The effect of glucocorticoids on the tissue biopsies will also be examined to discover the important pathways controlling energy expenditure in BAT. These studies will tell us whether blocking glucocorticoid action or other pathways in brown fat may increase energy expenditure in humans, and thereby treat obesity.

To assess macronutrient metabolism by human BAT, PET/CT scanning is currently the only available in vivo technique, but PET does not allow repeated measurements due to radiation exposure and only measures glucose uptake. We aim to measure cold-induced BAT lipid and glucose metabolism in healthy humans using three alternative techniques during stable isotope tracer infusion: 1) intra-adipose microdialysis and 2) selective venous cannulation of BAT (for arterio-interstitial and arterio-venous differences, respectively, in glucose/lipid uptake and energy production); and 3) 13C-magnetic resonance spectroscopy to measure TCA cycle activity. These in vivo techniques will be used to investigate the regulation of human BAT activity by glucocorticoids, which are potent suppressors of BAT in rodents. In parallel, we will use a protocol that we have established for primary culture of human brown adipocytes (obtained from patients undergoing elective neck surgery) to investigate glucocorticoid-sensitive pathways mediating effects on macronutrient metabolism and the role of local glucocorticoid regeneration by 11beta-hydroxysteroid dehydrogenase type 1. If successful, these tools will be vital to dissect BAT metabolic activity in human obesity, its control by other putative regulators, and the key transcription factors controlling differentiation, and to prove the concept that inhibiting glucocorticoid action increases BAT activity in humans.

Firstly, as stated in the academic beneficiaries, the results from this work will help advance the understanding of the importance and regulation of brown adipose tissue in humans. This will be of benefit to researchers from around the world, as one of the major barriers to developing activators of brown adipose tissue in humans is the unknown contribution of this tissue to whole body energy expenditure. We will utilise cutting edge techniques to investigate a field which has been technologically very challenging, and these tools once created can be used by other researchers/ individuals to dissect in vivo brown adipose tissue physiology.

The private sector will also benefit from this research, namely the pharmaceutical industry. Obesity is considered to be one of the greatest threats to health in the 21st century and research into drug therapies has mainly focused on increasing satiety (decreasing energy input) rather than promoting energy expenditure, and this research will highlight the potential of this alternative strategy. This research may also highlight new candidate pathways in brown adipose tisse which industry may be interested in targeting new drug development. This may lead to collaborations between academia and industry which is critical to improved health outcomes.

Research charities and the government will also benefit from research being performed in this field. A recent call to tackle obesity as one of the major health problems in the UK has highlighted the need for further work in this field. Therefore, being seen to fund research into obesity, which will be performed in the UK, will highlight that we are serious as a nation about exploring novel approaches to tackle this major health burden.

Beneficial effects of this fellowship to the wider population will take much longer to achieve than the duration of this 4-year fellowship. However, if the results from this body of work can either directly lead to new treatments or alternatively stimulate other researchers/ industry to create new drugs to treat obesity, this would be a major improvement for the nation's health as a whole.

Finally, the applicant and technician will benefit hugely from this work. Not only will this secure employment for both individuals for a significant 4-year period, the results generated from this fellowship will place the applicant in a strong position to secure a senior fellowship. In addition, the publications and impact from this work will form the foundation for further research which allow the applicant to expand his research team, providing additional employment and training for others (e.g. PhD students, post-doctoral staff) which can benefit the country as a whole.