Metabolomic Profiling of Long‐Term Weight Change: Role of Oxidative Stress and Urate Levels in Weight Gain

OBJECTIVE: To investigate the association between long‐term weight change and blood metabolites. METHODS: Change in BMI over 8.6 ± 3.79 years was assessed in 3,176 females from the TwinsUK cohort (age range: 18.3‐79.6, baseline BMI: 25.11 ± 4.35) measured for 280 metabolites at follow‐up. Statistically significant metabolites (adjusting for covariates) were included in a multivariable least absolute shrinkage and selection operator (LASSO) model. Findings were replicated in the Cooperative Health Research in the Region of Augsburg (KORA) study (n = 1,760; age range: 25‐70, baseline BMI: 27.72 ± 4.53). The study examined whether the metabolites identified could prospectively predict weight change in KORA and in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) study (n = 471; age range: 55‐74, baseline BMI: 27.24 ± 5.37). RESULTS: Thirty metabolites were significantly associated with change in BMI per year in TwinsUK using Bonferroni correction. Four were independently associated with weight change in the multivariable LASSO model and replicated in KORA: namely, urate (meta‐analysis β [95% CI] = 0.05 [0.040 to 0.063]; P = 1.37 × 10(−19)), gamma‐glutamyl valine (β [95% CI] = 0.06 [0.046 to 0.070]; P = 1.23 × 10(−20)), butyrylcarnitine (β [95% CI] = 0.04 [0.028 to 0.051]; P = 6.72 × 10(−12)), and 3‐phenylpropionate (β [95% CI] = −0.03 [−0.041 to −0.019]; P = 9.8 × 10(−8)), all involved in oxidative stress. Higher levels of urate at baseline were associated with weight gain in KORA and PLCO. CONCLUSIONS: Metabolites linked to higher oxidative stress are associated with increased long‐term weight gain.