GLP-1 应答不佳者的肝脏线粒体改变

Background The expanding use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has created a growing population of patients undergoing metabolic surgery after inadequate pharmacologic weight-loss response. Whether prior poor response is associated with distinct hepatic metabolic abnormalities or altered postoperative recovery is still unclear. Materials and Methods In this prospective observational study, 20 patients undergoing Roux-en-Y gastric bypass (RYGB) were enrolled, including 10 patients with GLP-1 receptor agonist-refractory obesity (GRO), operationally defined as less than 5% total body weight loss after at least six months of adequate GLP-1 RA therapy, and 10 GLP-1 RA-naive patients (GNO). Five lean individuals served as hepatic reference controls. Paired liver biopsies obtained during RYGB and approximately six months postoperatively were evaluated using histology, BODIPY fluorescence, transmission electron microscopy, and Western blot analysis of AMPK-ACC signaling and mitochondrial oxidative phosphorylation proteins. Results Baseline anthropometric and metabolic characteristics were broadly comparable between surgical cohorts. Nevertheless, GRO exhibited greater hepatic lipid accumulation, higher histological disease activity, more pronounced mitochondrial ultrastructural abnormalities, and reduced AMPK-ACC phosphorylation. Both cohorts achieved substantial six-month postoperative weight loss, although mean percentage total weight loss was lower in GRO than GNO (25.21% versus 29.51%). Paired tissue analyses demonstrated postoperative improvements in hepatic histology, lipid accumulation, and mitochondrial cristae integrity in both cohorts, with smaller improvements in GRO. Postoperative AMPK and ACC phosphorylation ratios remained lower in GRO, while mitochondrial protein analyses demonstrated complex-specific remodeling, including lower SDHB, UQCRC2, COX IV, and ATP5A abundance despite comparable NDUFS8 abundance at six months. Conclusions Prior poor GLP-1 RA weight-loss response was associated with distinct hepatic histological, energy-sensing, and mitochondrial characteristics among patients undergoing RYGB. Although substantial surgical weight loss occurred in both cohorts, differences in hepatic tissue recovery and molecular profiles persisted at six months. These exploratory findings warrant validation in larger cohorts incorporating pharmacologic responders and direct mitochondrial functional assessments.