A metabolomic signature of weight-loss and its associations with BMI-linked diseases: A post-hoc analysis of two intervention trials and a mendelian randomisation study

Abstract Background Obesity is a major risk factor for heart failure (HF), but the molecular mediators linking adiposity to HF remain unclear. The molecular mechanisms by which weight loss reduces the risk of HF are also unknown. Understanding these mechanisms could highlight potential therapeutic targets for all HF patients, including those who are normal weight. We aimed to identify a common metabolic perturbation profile by comparing different weight-loss interventions and to estimate their associations with HF using Mendelian randomisation (MR). Methods We first integrated mass spectrometry and nuclear magnetic resonance metabolomic profiling from two weight-loss interventions - a structured diet programme (DiRECT trial) and bariatric surgery (By-Band-Sleeve trial) - with estimates of the effect of life-time body mass index (BMI) exposure on metabolite levels through MR analyses, to identify a consistent BMI-metabolite signature across differing sources of BMI variation. We then assessed the impact of these BMI-metabolites on incident HF within a two sample MR framework. Results 1706 metabolites were analysed across three different sources of BMI variation: bariatric surgery, dietary intervention and life-time BMI exposure. 153 (9%) showed strong evidence for association with all three exposures with concordant direction of effect, predominantly comprising lipid fractions, lipoproteins, and amino acid metabolites. Among these metabolites, 44 (29%) had evidence of causal association with at least one HF subtype in MR. Notably, circulating levels of the non-lipid metabolites N-acetylglycine and asparagine were each inversely associated with BMI and with the risk of HF and HF with preserved ejection fraction risk, respectively. Both metabolites have previously been implicated in myocardial function and HF. Conclusions Our findings suggest that despite differences in the modality of weight loss delivery, there exists a consistent metabolomic profile coincident with weight change. Investigating the association of the identified metabolites with HF provides insights into molecular mediators of the effects of adiposity on HF and potential novel targets for therapeutic intervention.