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.

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.

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