In diet-induced obese Wistar rats with metabolic dysfunction-associated steatotic liver disease (MASLD), eight weeks of combined semaglutide plus PYY3-36 treatment produced additive reductions in hepatic inflammation and histological MASLD scores beyond either agent alone. RNA sequencing revealed coordinated downregulation of oxidative phosphorylation and beta-oxidation pathways, with OxPhos-related genes significantly suppressed in the combination group. PYY3-36 alone specifically reduced MCAD and PGC-1α expression — key beta-oxidation regulators — while the combination uniquely decreased mitochondrial H₂O₂ production and hepatocellular stress markers. Critically, caloric restriction producing equivalent weight loss showed no significant impact on mitochondrial respiration or OxPhos gene expression, suggesting these effects are pharmacologically direct rather than weight-loss mediated.
This mechanistic dissociation from weight loss is the most clinically significant signal here. Semaglutide's hepatic benefits have been attributed largely to weight reduction, but these data challenge that assumption and implicate direct mitochondrial signaling through GLP-1 and NPY2 receptors. The PGC-1α suppression finding is counterintuitive — PGC-1α is typically considered hepatoprotective — and warrants careful interpretation; in steatotic liver, pathologically elevated mitochondrial turnover may itself drive oxidative damage. Limitations are substantial: this is a small rodent study (n=7–17 per group), and translation to human MASLD remains unproven. Still, as combination incretin therapies enter clinical pipelines, this study offers a genuinely novel mechanistic framework — incremental but directionally important.