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Grape pomace (GP) is a by-product rich in phytochemicals, including extractable polyphenols (EPPs) and non-extractable polyphenols (NEPPs), which have distinct metabolic fates that may affect their biological activities. The benefits of GP have been reported in relation to obesity and its comorbidities, particularly when administered preventively focusing on EPPs. Therefore, the aim of this study was to investigate the effects of EPPs and NEPPs from GP as a treatment for obesity and its associated metabolic alterations. A previous comprehensive characterization of the selected GP revealed the most relevant individual compounds in the EPPs fraction (malvidin hexoside, (-)-epicatechin, quercetin, and procyanidin dimer B2 isomer II), as well as in the NEPPs fraction (hydroxybenzoic acid isomers I-II). The experiment was performed in obese rats with insulin resistance, treated for 8 weeks with EPPs or NEPPs grape pomace fractions (100 mg/kg). After the intervention, the HFFD + EPP group showed a significantly lower weight gain (9.6%) and body mass index (9.7%) compared to the HFFD group. While liver triglyceride levels were only significantly reduced in the HFFD + NEPP group (47%) compared to the HFFD group. Neither treatment resulted in a reduction of insulin resistance. Therefore, the supplementation with grape pomace phenolic fractions to an animal model of obesity exerted differential beneficial effects on body weight and liver lipid accumulation, overall contributing to an amelioration of some the metabolic alterations present in obesity, although not to aspects such as glycemic homeostasis., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)