W. Cawthorn, W. Cawthorn*a (Dr)

a University of Edinburgh, Edinburgh, ROYAUME-UNI

* W.Cawthorn@ed.ac.uk

Objective: Bone marrow adipose tissue (BMAT) represents >10% total fat mass in healthy humans and further increases in diverse clinical conditions. Like white adipose tissue (WAT), BMAT can produce hormones such as adiponectin, suggesting that it may exert systemic metabolic effects. Unlike WAT, BMAT increases in conditions of caloric restriction (CR), in which it is a key source of increased circulating adiponectin. Thus, BMAT appears developmentally and functionally distinct from WAT. However, the impact of BMAT on health and disease remains poorly understood. Thus, the objective of my research is to determine the fundamental functions and clinical significance of BMAT.

Methods: My lab’s research combines preclinical animal models, human clinical studies and data science approaches using the UK Biobank. Mouse models include CR studies in adiponectin knockout mice, to test if BMAT acts via adiponectin to influence the metabolic, skeletal and immunological effects of CR. Clinical studies include the use of positron emission tomography and computed tomography (PET-CT) to assess BMAT’s metabolic functions in vivo. Finally, we are using deep learning to analyse BMAT in magnetic resonance imaging data from the UK Biobank, thereby allowing us to identify the physiological, pathological and genetic factors associated with altered BMAT.

Results: 1) Adiponectin KO mice: We have found, unexpectedly, that lack of adiponectin enhances, rather than impairs, CR-induced improvements in glucose tolerance. Compared to wild-type counterparts, KO mice have lower fasting glucose during CR. Adiponectin KO also alters the immunological effects of CR. 2) PET-CT studies: in mice we find that BMAT glucose uptake is not insulin or cold-responsive, demonstrating that BMAT is metabolically distinct from WAT and brown adipose tissue. In humans we have found that BMAT has high basal glucose uptake under fasting conditions, greater even than that of skeletal muscle. Thus, BMAT may influence systemic metabolic homeostasis as a site of high glucose disposal. 3) UK Biobank studies: Our deep learning segmentations have yielded expected inverse associations between BMFF and bone mineral density (BMD) and identified new site- and sex-dependent relationships between BMFF, BMD and peripheral adiposity.

Discussion: Our preclinical and clinical studies have identified new fundamental functions of BMAT and adiponectin, including metabolic and immunological effects. In our UK Biobank studies we have developed and validated a new deep learning method for high-throughput BMFF analysis in the UKBB. Our initial results already provide new insights for the role of BMAT in skeletal and metabolic health. We have since analysed BMFF in ~37,000 subjects and are pursuing Genome- and Phenome-Wide Association Studies to identify genetic and pathophysiological factors associated with altered BMAT. Together, our research establishes the utility of machine learning for population-level BMFF analysis and promises to elucidate the full impact of BMAT on human health and disease.

William Cawthorn is an Associate Professor at the Centre for Cardiovascular Science, University of Edinburgh. His PhD research (Institute of Metabolic Science, University of Cambridge) investigated the regulation of adipogenesis while his postdoctoral studies (University of Michigan) focussed on mesenchymal cell fate and the function bone marrow adipose tissue (BMAT). In 2015 he established his laboratory at The University of Edinburgh with the overarching research goal of determining the function of BMAT. To do so his lab combines preclinical animal models, human clinical studies and data science approaches using the UK Biobank. Methods include in-depth metabolic phenotyping, immunological analyses, the development of novel biomedical imaging techniques, and artificial intelligence to open new avenues for population-level studies. Together, his research addresses the interplay between metabolism, immunological function and skeletal health, both in the context of fundamental biology and chronic diseases. He is a founding member and current Interim President of the International Bone Marrow Adiposity Society and is also the University of Edinburgh’s Open Science Ambassador for the League of European Research Institutions (LERU).

L’auteur n’a pas transmis de déclaration de conflit d’intérêt.