1207-OR: Early Plasma Metabolomic Adaptation during Dietary Interventions for Long-Term Weight Loss Success and Improved Cardiometabolic Health

Introduction and Objective: Maintaining long-term weight loss is challenging, and the underlying mechanisms remain unclear due to substantial individual variability. We developed a Metabolomic Adaptation Response (MAR) Index that integrates early metabolomic changes to predict long-term weight loss and examined whether plasma microRNAs from key metabolic organs influence the MAR. Methods: Untargeted plasma metabolomics were performed in 670 adults from the POUNDS Lost trial. Elastic net regression was applied to 834 metabolite changes from baseline to 6 months to predict 2-year weight loss using a 7:3 training/test split. Plasma microRNAs were measured by genome-wide sequencing. In an independent OmniCarb study (n=162), associations between MAR and diabetes physiology were examined. Results: A novel MAR based on 91 metabolite changes predicted long-term weight change (Figure). MAR was also associated with improvements in cardiometabolic abnormalities at 2 years. Changes in 25 microRNAs, including those related to the heart, liver, and obesity/diabetes, were associated with MAR levels (P-FDR < 0.05). In OmniCarb, a higher MAR identified obese adults with impaired glucose tolerance, reduced insulin sensitivity, and enhanced β-cell compensatory responses during a 2-hour OGTT. Conclusion: A composite index of early metabolite changes during dietary interventions predicts long-term weight loss and cardiometabolic improvement. Disclosure Y. Heianza: None. Q. Sun: None. D. Yu: None. F. Hu: None. L.J. Appel: Other - Payment for chapters in UpToDate on the relationship of hypertension with sodium, weight, exercise and smoking; Current; Wolters Kluwer. G. Bray: None. F.M. Sacks: None. L. Qi: None. Funding American Diabetes Association (7-25-ICTSAD-0480), National Institutes of Health (DK091718, DK100383, DK115679, 2P20GM109036-06A1)