{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:43:04Z","timestamp":1790775784787,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["15GRNT22420001"],"award-info":[{"award-number":["15GRNT22420001"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["11DK135630"],"award-info":[{"award-number":["11DK135630"]}]},{"name":"NIH","award":["DK132056"],"award-info":[{"award-number":["DK132056"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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\u2019s metabolic efficacy and long-term liver health.<\/jats:p>","DOI":"10.3390\/jcm15020479","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T14:02:51Z","timestamp":1767794571000},"page":"479","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Analysis of Roux-en-Y Gastric Bypass and High-Fat Feeding Reveals Hepatic Transcriptome Reprogramming: Ironing out the Details"],"prefix":"10.3390","volume":"15","author":[{"given":"Matthew","family":"Stevenson","sequence":"first","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, NYU Langone Hospital\u2013Long Island, 101 Mineola Blvd, Ste. 4-004, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0177-7925","authenticated-orcid":false,"given":"Munichandra Babu","family":"Tirumalasetty","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, NYU Langone Hospital\u2013Long Island, 101 Mineola Blvd, Ste. 4-004, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7872-2183","authenticated-orcid":false,"given":"Ankita","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, NYU Langone Hospital\u2013Long Island, 101 Mineola Blvd, Ste. 4-004, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3125-1238","authenticated-orcid":false,"given":"Qing","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, NYU Langone Hospital\u2013Long Island, 101 Mineola Blvd, Ste. 4-004, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collin","family":"Brathwaite","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, NYU Langone Hospital\u2013Long Island, 101 Mineola Blvd, Ste. 4-004, Mineola, NY 11501, USA"},{"name":"Department of Surgery, NYU Grossman Long Island School of Medicine, NYU Langone Hospital\u2013Long Island, 101 Mineola Blvd, Ste. 4-004, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8292-5159","authenticated-orcid":false,"given":"Louis","family":"Ragolia","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, NYU Langone Hospital\u2013Long Island, 101 Mineola Blvd, Ste. 4-004, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: Global epidemiology and pathogenesis","volume":"15","year":"2019","journal-title":"Nat. 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