Metabolomics Reveals Oxidative Stress Metabolites Involved in Long-term Weight Gain

The Challenge: Understanding the Molecular Pathways Associated with Long-term Weight Gain

Untargeted metabolomic profiling has provided considerable insight into the mechanisms and processes that drive excess weight gain in obese individuals. However, previous metabolomics research has leveraged mainly cross-sectional study designs, leaving an important gap in our understanding of alterations in obesity-related metabolites over time and how these metabolite changes impact long-term weight gain. To address this knowledge gap, researchers obtained longitudinal BMI data and performed untargeted metabolomic profiling on fasting blood samples from 3,176 females from the TwinUK study.

The Metabolon Insight: Linking Metabolites with Long-term Changes in Weight

To link metabolites with long-term weight changes, the researchers leveraged the Global Discovery Panel, which provides an unbiased view of all of the metabolites present in a sample, including amino acids, acylcarnitines, sphingomyelins, glycerophospholipids, carbohydrates, vitamins, lipids, nucleotides, peptides, xenobiotics, and steroids. The researchers applied linear regression analysis to link these metabolites with weight gain over ~9 years.

The Solution: A Role for Oxidative Stress Metabolites and Increased Weight Over Time

After adjusting for age, BMI at baseline, smoking, metabolite batch, and family relatedness, linear regression analyses revealed four metabolites independently associated with long-term weight change. Specifically, urate, gamma-glutamyl valine, and butyrylcarnitine exhibited positive associations with weight gain, while 3-phenylpropionate was negatively associated with weight gain.

These metabolites are not only altered in obesity and type-2 diabetes, but also play important roles in mediating oxidative stress. Notably, urate has been closely linked with increased risk of metabolic syndrome and is a marker for intracellular prooxidant and inflammatory status. Gamma-glutamyl valine is a widely used marker for elevated oxidative stress and also reflects glutathione turnover, a protective process against oxidative damage. Butyrylcarnitine is closely associated with insulin resistance, and high levels of butyrylcarnitine indicate incomplete beta-oxidation and a driver for increased reactive oxygen species (ROS). Finally, 3-phenylpropionate provides antioxidant effects, and decreased 3-phenylpropionate has been previously linked with weight gain.

To understand whether these metabolites might be predictive of future weight gain, the current report further investigated the interaction between baseline urate and changes in fatty acids within individuals who gained or lost weight, observing a positive association between urate, total fatty acids, and saturated fatty acids in individuals who gained weight. Conversely, lower polyunsaturated fatty acids were associated with elevated circulating urate in individuals who lost weight.

The Outcome: Insights into Metabolites Obesity Risk Indicators

These data provide important insights into the relationship between metabolite alterations and longitudinal body weight changes. Leveraging a large cohort study with untargeted metabolomics profiling revealed oxidative stress metabolites as novel indicators of long-term body weight changes, highlighting these metabolites as potentially robust biomarkers for identifying obesity risk, monitoring metabolic syndrome, and identifying novel therapeutic targets.