The association between body mass index and metabolite response to a liquid mixed meal challenge: a Mendelian randomization study.

BACKGROUND: Metabolite abundance is a dynamic trait that varies in response to environmental stimuli and phenotypic traits, such as food consumption and body mass index (BMI).

OBJECTIVES: Here we use the Netherlands Epidemiology of Obesity (NEO) study to identify observational and causal associations between BMI and metabolite response to a liquid meal.

METHODS: A liquid meal challenge was performed and Nightingale Health metabolite profiles were collected in 5744 NEO participants. Observational and one-sample MR analysis were conducted to estimate the effect of BMI on metabolites (n = 229) in the fasting, postprandial and response (or change in abundance) states.

RESULTS: We observed 473 associations with BMI (175 fasting, 188 postprandial, 110 response) in observational analyses. In MR analyses, we observed 20 metabolite traits (5 fasting, 12 postprandial, 3 response) to be associated with BMI. MR associations included the glucogenic amino acid alanine which was inversely associated with BMI in the response state (beta = -0.081, se = 0.023, P = 5.91x10-4 ), suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI.

CONCLUSIONS: Overall, MR estimates were strongly correlated with observational effect estimates suggesting that the broad associations seen between BMI and metabolite variation has a causal underpinning. Specific effects in previously unassessed postprandial and response states were detected and these may likely mark novel life course risk exposures driven by regular nutrition.