Analysis of Roux-en-Y Gastric Bypass and High-Fat Feeding Reveals Hepatic Transcriptome Reprogramming: Ironing out the Details

<b>Background/Objectives:</b> Roux-en-Y gastric bypass (RYGB) improves obesity-related metabolic disorders, yet post-operative dietary composition critically shapes outcomes. This study explored how RYGB and high-fat diet (HFD) differentially regulate hepatic transcriptional programs. <b>Methods:</b> We performed RNA-seq on liver tissues from diet-induced obese C57BL/6 male mice 8 weeks post-RYGB or sham surgery, maintained on chow or HFD. Differentially expressed genes (DEGs) were identified using DESeq2. Gene sets were categorized as RYGB-induced (commonly regulated by surgery across diets), Reversal (RYGB-driven counter-regulation of obesity-induced changes), and HFD-induced (commonly regulated by diet). A subset of RYGB-specific HFD-induced genes was derived by excluding HFD-induced genes from the RYGB Chow vs. RYGB HFD contrast. Pathway enrichment was conducted using STRING. <b>Results:</b> RYGB induced 365 DEGs, including pathways related to extracellular remodeling and reduced mitochondrial/antioxidant activity. Among these, 119 Reversal genes countered obesity-associated transcriptional patterns and accounted for ~27% of the RYGB-induced enrichment results. HFD regulated 860 DEGs, highlighting stress responses and translational repression. Lastly, a set of 426 RYGB-specific HFD-induced genes revealed persistent hepatic inflammation, coagulation, and iron dysregulation under HFD despite surgery. <b>Conclusions:</b> RYGB induces robust hepatic transcriptomic changes that attenuate obesity-driven dysregulation, including a coordinated reprogramming of iron-handling pathways. However, high dietary fat partially overrides these benefits, promoting inflammatory, metabolic stress, and iron-related stress. Optimizing post-operative diets and carefully managing micronutrient intake, especially iron, may enhance RYGB's metabolic efficacy and long-term liver health.