Rosiglitazone Ameliorates Adverse Effects of High-Fat Diet in Largemouth Bass (Micropterus salmoides): Modulation of Lipid Metabolism, Antioxidant Capacity, Inflammatory Response, and Gut Microbiota

High-fat (HF) diets are widely used in aquaculture to reduce feed costs, but they often lead to hepatic steatosis, oxidative stress, and reduced environmental tolerance in carnivorous fish. This study evaluated whether dietary rosiglitazone (RO; 10 mg·kg^-1) alleviates HF (18% fat) diet-induced metabolic dysfunctions in juvenile largemouth bass (<i>Micropterus salmoides</i>). Fish were fed a control diet (10% fat), an HF diet (18% fat), or an HF + RO diet for 8 weeks. RO supplementation reversed HF-induced dyslipidemia by lowering plasma triglyceride (TG) and total cholesterol (T-CHO) while elevating high-density lipoprotein cholesterol (HDL-c), and it reduced intraperitoneal fat and whole-body lipid (<i>p</i> < 0.05). RO also mitigated hepatic vacuolization and decreased plasma alanine aminotransferase (ALT) (<i>p</i> < 0.05) and aspartate aminotransferase (AST) (<i>p</i> > 0.05) activities. Antioxidant capacity was enhanced by RO, as indicated by increased glutathione (GSH), catalase (CAT), and total antioxidant capacity (T-AOC), together with reduced malondialdehyde (MDA), and accompanied by upregulation of <i>nrf2</i>, downstream antioxidant genes, and downregulation of <i>keap1</i> (<i>p</i> < 0.05). Moreover, RO suppressed HF-induced endoplasmic reticulum (ER) stress (<i>grp78</i>, <i>eif2α</i>, <i>chop</i>) and pro-inflammatory genes (<i>tnfα</i>, <i>il-1β</i>, <i>nf-κb</i>), while upregulating <i>il-10</i> (<i>p</i> < 0.05). Gut microbiota analysis showed RO-mediated enrichment of Firmicutes and short-chain fatty acid-producing genera (<i>Faecalibaculum</i>, <i>Dubosiella</i>). Importantly, RO significantly reduced mortality during a 96 h acute ammonia challenge (<i>p</i> < 0.05). Collectively, these results demonstrate that dietary rosiglitazone mitigates HF diet-induced hepatic oxidative stress and metabolic dysregulation through Nrf2 activation, anti-inflammatory effects, and microbiota modulation, providing a potential strategy to enhance HF feed utilization and environmental stress resilience in carnivorous fish. Further studies on dose optimization and residue safety are warranted.