What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping.

BMI is a measure of adiposity calculated as weight adjusted for height squared. There are clear observational associations between BMI and health including all cause mortality cardiovascular disease, type-2-diabetes and cancer. However, it remains extremely difficult to change and maintain BMI and major gaps exist in understanding why BMI is a risk factor. Circulating metabolites are the product of genetic and non-genetic factors and are a useful read-out of physiological function. Using metabolomic measurements to identify possible routes between BMI and disease has great potential for understanding the mechanisms of effect suggesting targets for therapy development. Metabolome-wide measurement from complementary platforms will be collected for samples from two randomised control trials, a meal challenge study and two studies of the human faecal microbiome. I will characterise the impact of BMI on specific measures within these independent studies and use additional population based resources to triangulate evidence across them. I will update the limited existing lists of BMI driven metabolites and lastly examine evidence for causal effects of BMI driven metabolites on disease using efficient multi-study methods. This will identify target BMI-metabolites which will focus future translational research and the activity of my own applied study designs in other research streams.