Caffeic acid phenethyl ester induces healthy expansion of adipose tissue and protects against Aeromonas hydrophila infection via p65-dicentracin pathway in high-carbohydrate diet-fed largemouth bass (Micropterus salmoides).

High-carbohydrate diet (HCD) is widely used in aquaculture to reduce protein costs, but it often induces pathological adipose tissue hypertrophy, chronic inflammation, and increased susceptibility to bacterial infections. This study investigated whether dietary supplementation with caffeic acid phenethyl ester (CAPE) could alleviate HCD-induced pathological adipose tissue hypertrophy and enhance resistance against Aeromonas hydrophila in largemouth bass (Micropterus salmoides), and explored the underlying mechanisms. Fish were fed a control diet, an HCD, or HCD supplemented with CAPE (400, 800, or 1200 mg/kg) for eight weeks, followed by bacterial challenge. HCD impaired growth, promoted adipocyte hypertrophy and visceral fat accumulation, and triggered inflammation and oxidative stress. CAPE reversed these effects, shifting adipose expansion toward hyperplasia, improving lipid and glucose metabolism, reducing inflammatory markers and ROS, and markedly improving survival after infection. The three CAPE doses exhibited comparable efficacy across all measured parameters, with the lowest dose (400 mg/kg) already achieving maximal benefits. Mechanistically, CAPE suppressed HCD-induced NF-κB p65 activity via PPARγ activation, and we identified the antimicrobial peptide dicentracin as a direct transcriptional target repressed by p65. CAPE relieved this repression, restoring dicentracin expression and antibacterial defense. Collectively, CAPE decouples metabolic stress from immune suppression through PPARγ-mediated relief of p65 repression. These findings reveal a novel p65-dicentracin axis linking adipose tissue expansion mode to antibacterial immunity, and highlight CAPE as a promising immunometabolic feed additive to address both metabolic stress and infectious diseases in aquaculture.