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
by Nicholas Sunderland, Madeleine L. Smith, Alex McConnachie, Paul Welsh, Roy Taylor, Michael E. J. Lean, Chris A. Rogers, Jane M. Blazeby, Naveed Sattar, Lavinia Paternoster, R. Thomas Lumbers, Nicholas J. Timpson, Laura J. Corbin Background Obesity is a major risk factor for a broad spectrum of diseases, yet the molecular pathways underlying this risk remains poorly understood. Individual…
The study conducted by a team of researchers sought to uncover a shared metabolic signature associated with adiposity, as well as its relationship with various obesity-related health conditions. The researchers utilized data from two separate weight-loss interventions, namely the DiRECT trial and the By-Band-Sleeve trial, alongside metabolomic profiling obtained through mass spectrometry and nuclear magnetic resonance techniques.
Additionally, they leveraged mendelian randomisation estimates to explore the impact of lifetime BMI on metabolite levels across distinct sources of data.
Through this comprehensive approach, the researchers identified a consistent metabolic signature across the two interventions, which primarily comprised alterations in lipids, lipoproteins, and amino acids. These changes were predominantly driven by adiposity and were consistent with the regulation of these metabolic pathways by body mass index (BMI).
Subsequently, the adiposity-associated metabolites were instrumented using genetic variants, and their associations with heart failure (HF), osteoarthritis, and kidney cancer were examined using a two-sample Mendelian randomisation framework.
The findings revealed that certain metabolic components of this signature were linked to disease-specific outcomes. For example, low-density lipoprotein (LDL) cholesterol measures were strongly associated with an increased risk of heart failure, consistent with the enrichment of ischaemic aetiology. Conversely, high-density lipoprotein (HDL) cholesterol-enrichment traits exhibited a protective effect against heart failure, while markers of dysfunctional HDL remodelling were associated with elevated risk.
In the case of osteoarthritis, the adiposity metabolite signature demonstrated an inverse relationship with disease risk, alongside additional signals observed in glycine metabolism pathways. However, the metabolite signature translated poorly into associations with kidney cancer, with only a few significant associations identified, such as those involving 5-methyluridine and ursodeoxycholate.
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