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

## TL;DR

Gastric bypass surgery changes liver genes to counter obesity effects, but a high-fat diet after surgery can undo these benefits and cause liver stress and iron imbalance.

## Contribution

The study identifies distinct gene sets regulated by RYGB and HFD, revealing how diet quality affects post-surgery liver health.

## Key findings

- RYGB reverses obesity-linked transcriptional changes through 119 Reversal genes.
- High-fat diet after RYGB causes liver inflammation, stress, and iron dysregulation.
- Diet quality post-RYGB is critical for sustaining metabolic and liver benefits.

## Abstract

RYGB alters liver genes, reversing obesity-linked transcriptional changes.

HFD after RYGB triggers liver stress, inflammation, and iron imbalance.

Diet quality post-RYGB is key to sustaining liver and metabolic benefits.

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.