Bone marrow adipose tissue as a novel regulator of metabolic homeostasis

Stop and think about your bones; what images come to mind? Perhaps a skull with grinning jaws, or the strong white limbs stretching from your hips to your toes. You might even think of the bone marrow within them, producing the blood that courses through your veins. But this is not the whole picture, for your skeleton hides a secret: it is full of fat, and no one knows why.

This unsolved mystery is surprising. Scientists first noticed that our bone marrow contains fat-storing cells, called adipocytes, over a century ago. Having fat in our bones might strike you as unusual, but it is not: bone marrow adipose tissue (MAT) makes up to 70% of bone marrow volume in healthy adults, suggesting that MAT has a role in normal human physiology. MAT further increases in conditions of altered bone formation or metabolic health. For example, increased MAT occurs in osteoporosis, suggesting that MAT might contribute to the bone fragility that defines this disease. Perhaps most bizarrely, MAT formation increases in starvation states, such as during caloric restriction in animals or in human patients with anorexia nervosa. This is in stark contrast to adipose tissue elsewhere in the body, called white adipose tissue (WAT), which is broken down during starvation to be used as fuel. Caloric restriction has numerous health benefits, including increased lifespan, decreased risk of cancer and cardiovascular disease, and metabolic benefits such as enhanced fat breakdown and insulin sensitivity. MAT also increases in response to treatment with anti-diabetic drugs, which, like caloric restriction, enhance insulin sensitivity. These clinical observations raise the possibility that MAT directly promotes insulin sensitivity and metabolic health. But unlike WAT, almost nothing is known about the biological function of MAT.

The possibility that MAT exerts metabolic benefits could have enormous implications for human health. Metabolic diseases such as diabetes currently place a huge burden on public health, both in the UK and around the globe. One in seventeen adults in the UK, or 3.2 million people, now has diabetes, and this is expected to rise to 4.6 million people by 2030. This is causing a major strain on the economy, costing the NHS over £1.5 million an hour, or 10% of the NHS budget for England and Wales. In total, an estimated £14 billion is spent a year on treating diabetes and its complications in the UK. Globally, diabetes cost £232 billion in 2010, and this is projected to increase to over £300 billion by 2030. Identifying new treatments for diabetes and its complications would therefore provide a massive benefit to human health worldwide. However, developing such treatments requires improved understanding of the factors that regulate insulin sensitivity and metabolic health. This leads us back to MAT. What controls MAT formation, and does MAT benefit metabolic health?

A team of scientists at the University of Edinburgh is now working to answer these key questions. Members of this research team recently found that, during caloric restriction, MAT is a key source of adiponectin, a hormone that helps to maintain insulin sensitivity and fat breakdown, and which is linked to decreased risk of obesity-associated cancers, cardiovascular disease and diabetes. The University of Edinburgh team will now build on this research by studying why MAT expands during caloric restriction and investigating if MAT affects our metabolic health. Finally, these researchers will study samples of MAT and WAT provided by human donors to determine precisely how MAT differs to WAT in humans.

These studies will help to unravel the mystery of MAT. In doing so, this research might allow the development of new treatments for diabetes and its complications, as well as other diseases including osteoporosis, cardiovascular disease and some cancers. This will be vital if we are to reduce the public health impact of these globally relevant health problems.

Bone marrow adipose tissue (MAT) comprises up to 70% of bone marrow volume in healthy adults and further increases under conditions of altered metabolic homeostasis, such as caloric restriction (CR). My previous research identifies MAT as an endocrine organ that has systemic effects. These observations suggest that MAT directly impacts metabolic homeostasis, knowledge that might reveal new approaches for treating diabetes and other metabolic diseases. However, in stark contrast to white or brown adipose tissues (WAT or BAT), study of MAT has been extremely limited; hence, the physiological and pathological roles of MAT are poorly understood. My research will address this major gap in knowledge by investigating the characteristics, formation and metabolic function of MAT. My first objective is to establish unique MAT characteristics. To do so I will use RNAseq, proteomics and metabolomics to globally characterise MAT, WAT and BAT from rats, followed by targeted analysis of these tissues from humans. This will provide crucial insights into MAT biology directly relevant to human health. My second objective is to determine if increased glucocorticoid action mediates MAT expansion during CR. To do so I will use surgical and pharmacological tools to block glucocorticoid activity in mice fed control or CR diets. This will shed new light on why CR causes MAT expansion. My third objective is to determine if MAT impacts metabolic homeostasis. To do so I will create a new mouse model that lacks MAT. I will then study these mice to determine if lack of MAT has metabolic consequences, both on a normal diet and during CR. Finally, my fourth objective is to establish new mouse models for specific, inducible genetic targeting of MAT. These unique models will open avenues for future research to shed new light on MAT formation and function. Such knowledge might reveal new mechanisms of metabolic regulation, thereby allowing development of new strategies to treat metabolic diseases.

My research will hugely extend our knowledge of MAT formation and function while also establishing new experimental tools to open avenues for future cutting-edge research. This new knowledge might advance understanding and treatment of diverse clinical conditions, including type 2 diabetes, cardiovascular disease, osteoporosis, haematopoietic disorders, metastatic bone disease, and various cancers. Thus, the results of my research will have broad translational potential, including the following beneficiaries:

1) Pharmaceutical arms of the commercial sector - My results could allow the development of new treatments for the above diseases. For example, my research will reveal if MAT regulates insulin sensitivity. If so, then MAT might directly contribute to the effectiveness of FGF21, an emerging anti-diabetic therapy that promotes MAT expansion. Thus, the results of my research have clear potential to impact drug development. Indeed, my previous MAT research was partly funded by partners in the pharmaceutical industry, underscoring the strong translational potential of my work.

2) The NHS and public health policy-makers - Improved knowledge of MAT function could benefit clinical approaches to diagnose and treat the diverse diseases listed above, which in turn could allow for more effective public health strategies. For example, MAT is emerging as an important clinical indicator for increased fracture risk, and therefore could be used as a biomarker to identify high-risk individuals. My research will reveal if MAT also exerts systemic metabolic effects, in which case increased MAT might be associated with improved cardiometabolic health. Such knowledge would better inform clinicians and public health policy-makers in using MAT as a clinical biomarker. Moreover, my work will reveal if glucocorticoid excess promotes MAT expansion and/or bone loss during caloric restriction. This knowledge is clinically relevant to bone loss during anorexia nervosa, a condition that remains incompletely understood. Therefore, these results could directly benefit clinical practice within the five-year timeframe.

3) The wider public - New disease treatments and improved clinical practice would greatly benefit the wider public. For example, diabetes currently places a huge burden on public health, affecting 6% of UK adults, or 3.2 million people. This is a huge detriment to the economy, with an estimated £14 billion spent a year on treating diabetes and its complications in the UK. Identifying new treatments for diabetes and its complications would therefore hugely benefit the UK economy and the health of the wider public.

4) Staff working on this project - In pursuing this research I will supervise and mentor my lab members, who will develop transferable skills such as communication, teamwork and time-management. I will develop skills including project- and financial-management, leadership and mentoring. Thus, my lab members and I will develop professional skills that are essential for success in many employment sectors.

Within the five-year timeframe we will have established the unique characteristics of MAT compared to WAT and BAT, including analysis of human tissues to ensure direct relevance to human health. We will have determined if excess glucocorticoids contribute to MAT expansion and bone loss during caloric restriction. We will have revealed if MAT impacts metabolic homeostasis, laying a foundation for development of new treatments for metabolic disease. Finally, we will have established new mouse models for specific, inducible MAT targeting, thereby opening avenues for future research to more precisely dissect MAT function. Such research will allow us to establish if MAT directly impacts the diverse clinical conditions described above, which will aid progress toward meeting these extensive unmet clinical needs.