GLP-1 Refractory Obesity Is Associated with Inferior Weight Loss After Bariatric Surgery and a Distinct Hepatic Mitochondrial Phenotype

The study examined patients with GLP-1 refractory obesity (GRO) who lost less than 5% of their body weight despite 12 months of GLP-1 receptor agonist therapy. Researchers compared hepatic tissue from GRO patients, GLP-1 naive obese patients (GNO), and healthy controls. GRO patients exhibited more advanced hepatic steatosis, fibrosis, and mitochondrial disruption compared to GNO patients. Molecular analyses revealed marked suppression of GLP-1 receptor signaling (75-85%) and oxidative phosphorylation complexes (38-55%) in GRO patients. Following bariatric surgery, GRO patients achieved lower weight loss (25.2% versus 29.51% total weight loss; P<0.001) compared to GNO patients. The results suggest that GLP-1 refractory obesity represents a biologically distinct metabolic phenotype with mitochondrial and signaling impairments.