Dissecting the molecular mechanisms by which Bmp8b increases thermogenesis in brown adipose tissue.

Brown adipose tissue (BAT) is a unique tissue in that whilst it resembles traditional white adipose tissue in some ways it exists to burn fat rather than store it. Evolutionarily, BAT emerged as a way of generating heat to defend body temperature in cold conditions and order to perform this role it developed a number of specialized characteristics. BAT is heavily under the control of the sympathetic nervous system (SNS), to the degree that every single brown adipocyte receives neuronal input. This is so that the tissue can respond quickly to environmental demand, increasing mitochondrial content, mobilizing stored fat and oxidising large amounts of it to generate heat. To meet the demand placed on it BAT can expand in mass incredibly quickly, doubling in size and generating new nerves and blood vessels to supply it with the nutrients and control it requires. How all of these processes are activated, regulated and maintained is not understood but the mechanisms may be relevant to the regeneration of a range of tissues, for example veins, nerves and even liver.

We have discovered a molecule that is secreted into and around active BAT, which believe plays a crucial role in a number of processes. Our preliminary evidence suggests that bone morphogenetic protein 8b (BMP8b) is able to increase BAT sensitivity to activation by the SNS whilst directly regulating the growth of neurons and vascular cells. In addition, we have reason to believe that BMP8b also acts at a central level, regulating pathways in the brain that respond to environmental and dietary changes in order to increase SNS activation of BAT at the periphery. Understanding how a secreted molecule can elicit such specific effects in diverse cell types is likely to uncover new molecular pathways that co-ordinate the remodeling of mature tissues and their metabolic activity. It is also likely to lead to the generation of new targets for drug development in a range of diseases, even those mediated by aberrant sympathetic nervous system activity.

The potential benefits that may come from understanding the functions of BMP8b are not just extremely interesting from a molecular biology perspective. Recent studies have shown unequivocally that adult humans possess substantial quantities of brown fat. It may be that endogenous mechanisms such as Bmp8b exist in humans for activating BAT and increasing energy expenditure. In the face of a widening obesity epidemic, the ability to redress the positive energy balance that causes the disease would be extremely desirable.

Brown adipose tissue is unique in its high oxidative capacity, mitochondrial content, sympathetic innervation and finally its ability to undergo rapid hyperplasia. The mechanisms regulating all of these processes, in a manner which coordinates multiple cell types are largely unknown in the mature organism. Bone morphogenetic proteins (BMPs) have been characterised as developmental factors that control cell differentiation and tissue organisation in embryogenesis. Bmp8b has two important features, distinct from other BMPs acting in adipose tissue. First, it is highly cold-inducible and second, it is expressed principally in mature brown adipocytes. Our preliminary data indicate that BMP8b is induced by cold in both classical brown and white depots in proportion to their capacity to form brown adipocytes. Mice over-expressing Bmp8b have increased thermogenic genes in subcutaneous WAT and levels of Bmp8b in vivo correlate with levels of neurogenic and angiogenic markers. Also, neuronal cells cultured ex vivo display increased growth and survival when treated with Bmp8b, suggesting BMP8b drives at least 2 of the three major processes (adipogenesis, neurogenesis and angiogenesis) involved in brown adipose tissue remodeling in response to cold. Through these processes and potentially also via its central actions, Bmp8b is able to regulate global energy balance, whereby Bmp8b -/- mice are susceptible to obesity.

We aim to dissect the mechanism of action of Bmp8b by examining transctriptomic alterations in BAT and WAT of in vivo in models with altered Bmp8b expression levels. Combined with proteomic analysis in cell models in vitro we aim to identify the specific signaling pathways through which Bmp8b regulates adipocytes, neurons and endothelial cells. We will also use virally mediated, nuclei-specific manipulation of Bmp8b in the brain to assess the relative contribution of central and peripheral Bmp8b to energy balance and again aim to identify its mode of action.

Medicine and Pharmaceutical Industry: Agonists of adrenergic receptors have been used successfully in the past to increase energy expenditure and treat metabolic disorders, however a lack of specificity has resulted in detrimental cardiovascular effects and the ultimate withdrawal of these drugs. Bmp8b represents a molecule that appears to act downstream of adrenergic receptors, opening up a novel molecular target (once the mechanism is better defined) for modulating the sympathetic nervous system sensitivity of specific tissues. Obviously, the role of Bmp8b in energy balance shown in our previous data makes it an attractive mechanism by which to examine the activation of human BAT, for the treatment of obesity. We already have strong links with UK based pharma companies as outlined in our proposal and as such our work could culminate in the generation of products which were of economic benefit to the UK as well as a health benefit to UK citizens.

Farmers: The ability to manipulate endogenous pathways that regulate energy balance may enable farmers to improve efficiency in terms of meat/dairy production offset to feed costs. In addition, the ability to enhance thermogenesis may improve survival and welfare in species reared outdoors in cold climates. In an increasingly competitive and highly subsidised industry, such advances would provide a economic benefit to the UK economy.

Food industry: Understanding how nutritional signals are integrated at a central level with activation/suppression of thermogenesis in BAT is likely to suggest dietary approaches to maintaining elevated energy expenditure in BAT. This is likely to be attractive to the "functional food" producers such as those making existing products enriched in omega3 fatty acids. Such products might offer a low-cost way to improve health and well-being in the UK without investment from central government. At the same time the products may themselves represent an economic benefit to the UK

Public health education: Our research could provide scientific background for public education on environmental and dietary stimulation of BAT to improve resistance to diet induced obesity. This could represent a significant benefit to public health and wellbeing.

The timescale for impact on most of the above is realistically in the order of 5-8 years for maximal effectiveness. However in the meantime the project will provide technological advances in real-time on an annual basis and provide a post-doctoral researcher (AW) with the skill necessary to advance his career to the young investigator stage. These skill would also be transferable to the private sector/pharma industry.