Objective:To evaluate the synergic effects of a novel oral supplement formulation,containing prebiotics,yeast β-glucans,minerals and silymarin (Silybum marianum),on lipid and glycidic metabolism,inflamma-tory and mitochondrial proteins of the liver,in control and high-fat diet-induced obese mice.Methods:After an acclimation period,32 male C57BL/6 mice were divided into the following groups:nonfat diet (NFD) vehicle,NFD supplemented,high-fat diet (HFD) vehicle and HFD supplemented.The vehicle and experimental formulation were administered orally by gavage once a day during the last four weeks of the diet (28 consecutive days).We then evaluated energy homeostasis,inflammation,and mito-chondrial protein expression in these groups of mice.Results:After four weeks of supplementation,study groups experienced reduced glycemia,dyslipidemia,fat,and hepatic fibrosis levels.Additionally,proliferator-activated receptor-x,AMP-activated protein kinase-1α,peroxisome proliferator-activated receptor y co-activator-1α,and mitochondrial transcription factor A expression levels were augmented;however,levels of inhibitor of nuclear factor-κB kinase sub-unit α and p65 nuclear factor-κB expression,and oxidative markers were reduced.Notably,the cortisol/C-reactive protein ratio,a well-characterized marker of the hypothalamic-pituitary-adrenal axis immune interface status,was found to be modulated by the supplement.Conclusion:We discovered that the novel supplement was able to modify different antioxidant,meta-bolic and inflammatory pathways,improving the energy homeostasis and inflammatory status,and con-sequently alleviated hepatic steatosis.