Proteome‐wide associations with short‐ and long‐term weight loss and regain after Roux‐en‐Y gastric bypass surgery

OBJECTIVE: Gastric bypass surgery results in long‐term weight loss. Small studies have examined protein changes during rapid weight loss (up to 1 or 2 years post surgery). This study tested whether short‐term changes were maintained after 12 years. METHODS: A 12‐year follow‐up, protein‐wide association study of 1,297 SomaLogic aptamer‐based plasma proteins compared short‐ (2‐year) and long‐term (12‐year) protein changes in 234 individuals who had gastric bypass surgery with 144 nonintervened individuals with severe obesity. RESULTS: There were 51 replicated 12‐year protein changes that differed between the surgery and nonsurgery groups. Adjusting for change in BMI, only 12 proteins remained significant, suggesting that BMI change was the primary reason for most protein changes and not non‐BMI‐related surgical effects. Protein changes were related to BMI changes during both weight‐loss and weight‐regain periods. The significant proteins were associated primarily with lipid, uric acid, or resting energy expenditure clinical variables and metabolic pathways. Eight protein changes were associated with 12‐year diabetes remission, including apolipoprotein M, sex hormone binding globulin, and adiponectin (p < 3.5 × 10(−5)). CONCLUSIONS: This study showed that most short‐term postsurgical changes in proteins were maintained at 12 years. Systemic protection pathways, including inflammation, complement, lipid, and adipocyte pathways, were related to the long‐term benefits of gastric bypass surgery.