GLP-1 Refractory Obesity Is Associated with Inferior Weight Loss After Bariatric Surgery and a Distinct Hepatic Mitochondrial Phenotype
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Background
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are first-line pharmacotherapy for obesity and metabolic dysfunction-associated steatotic liver disease (MASLD); however, 20–35% of patients fail to achieve clinically meaningful weight loss despite guideline-directed therapy. Whether this GLP-1 refractory obesity (GRO) phenotype is associated with distinct hepatic molecular abnormalities or influences bariatric surgical outcomes remains unknown.
Objectives
To characterize the hepatic histological, ultrastructural, and molecular phenotype of GRO at bariatric surgery, determine its recovery following surgery, and identify preoperative hepatic biomarkers associated with postoperative weight loss.
Setting
Academic tertiary referral bariatric surgery center.
Methods
Intraoperative liver biopsies were obtained from lean controls (n=3), GLP-1-naïve obese patients (GNO; n=10), and GLP-1-refractory obese patients (GRO; n=10) undergoing Roux-en-Y gastric bypass. GRO was defined as <5% total weight loss after ≥12 months of guideline-directed GLP-1 RA therapy. Paired liver biopsies were obtained six months postoperatively from subsets of GNO (n=5) and GRO (n=5). Histological, ultrastructural, and molecular analyses were performed, and preoperative hepatic protein expression was correlated with postoperative total weight loss.
Results
Compared with GNO, GRO patients exhibited more advanced hepatic steatosis, fibrosis, lipid accumulation, and mitochondrial ultrastructural disruption at surgery (all P<0.05). Despite equivalent BMI, GNO patients maintained lean-equivalent hepatic pCREB, pAMPK, pACC, and oxidative phosphorylation (OXPHOS) protein expression, whereas GRO patients demonstrated marked suppression of GLP-1R downstream signaling (75–85%) and OXPHOS complex subunits (38–55%; all P<0.001). Six months after surgery, histological and molecular recovery remained significantly attenuated in GRO. GRO patients achieved less postoperative weight loss than GNO patients (25.2±1.5% vs. 29.5±1.5% total weight loss; P<0.001). Across the pooled cohort, several hepatic molecular markers correlated with postoperative weight loss; however, no individual biomarker independently predicted postoperative weight loss within the GRO subgroup.
Conclusions
GLP-1 refractory obesity is associated with a distinct hepatic phenotype characterized by impaired GLP-1R signaling, mitochondrial dysfunction, and attenuated hepatic recovery following bariatric surgery. The coordinated suppression of hepatic energy-sensing, mitochondrial biogenesis, and oxidative phosphorylation pathways supports the concept that GLP-1 refractory obesity represents a biologically distinct metabolic phenotype. Larger prospective studies are required to determine the prognostic utility of hepatic molecular profiling for postoperative outcomes.
