GAMMA-ORYZANOL ATTENUATES HEPATIC METABOLIC REMODELING IN HIGH SUGAR-FAT DIET-INDUCED OBESITY MODEL: A 1H NMR-BASED METABOLOMICS APPROACH

Obesity is a multifactorial metabolic disorder characterized by excessive adipose tissue accumulation and chronic metabolic imbalance, contributing to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatic metabolic remodeling induced by obesity involves disturbances in mitochondrial function, energy metabolism, and redox homeostasis, favoring oxidative stress and tissue dysfunction. Gamma-oryzanol (ORY), a bioactive phytochemical with antioxidant and anti-inflammatory properties, has emerged as a promising nutritional strategy for improving obesity-associated metabolic dysfunction. Therefore, this study aimed to investigate the effects of ORY supplementation on the hepatic metabolomic profile of rats with high sugar-fat (HSF) diet-induced obesity. Male Wistar rats were fed a control (CTRL), HSF (34.2% energy from fat and 49.2% from carbohydrates, including sucrose and fructose), or HSF supplemented with 0.5% (w/w) ORY for 30 weeks (CEUA 1451/2024). Nutritional and metabolic parameters were evaluated. Hepatic metabolites were extracted using methanol/chloroform and analyzed by proton nuclear magnetic resonance (^1H NMR), followed by metabolite identification and quantification using Chenomx software. Statistical analyses were performed using one-way ANOVA followed by Tukey’s post hoc test (α = 0.05) and false discovery rate (FDR)-adjusted comparisons. HSF feeding induced obesity, insulin resistance, dyslipidemia, hepatic steatosis, and significant alterations in metabolites involved in energy metabolism, nucleotide turnover, and redox homeostasis. ORY supplementation attenuated these metabolic disturbances, improving obesity, insulin resistance, dyslipidemia, and hepatic steatosis while partially restoring the hepatic metabolomic profile. Compared with CTRL, HSF animals exhibited increased hepatic levels of 3-hydroxybutyrate (p = 0.017), creatine phosphate (p = 0.023), formate (p = 0.008), glutamine (p = 0.019), hypoxanthine (p = 0.003), and pyroglutamate (p = 0.031), whereas ATP (p = 0.016), NADP+ (p = 0.013), UDP-glucose (p = 0.021), and xanthosine (p = 0.037) were reduced. Collectively, these alterations are consistent with impaired mitochondrial bioenergetics, enhanced nucleotide turnover, and disrupted hepatic redox homeostasis, hallmarks of obesity-induced hepatic metabolic remodeling. Moreover, ORY partially restored the obesity-induced metabolic profile by reducing hepatic 3-hydroxybutyrate (p = 0.008), glutamine (p = 0.001), lactate (p = 0.035), and succinate (p = 0.032), while also decreasing creatine (p = 0.033), choline (p = 0.014), and lysine (p < 0.001), suggesting improved mitochondrial energy metabolism and broader modulation of hepatic metabolic pathways. Overall, ORY attenuated obesity-induced metabolic dysfunction by reducing obesity, insulin resistance, dyslipidemia, hepatic steatosis, and hepatic metabolic remodeling, supporting its potential as a nutritional strategy to mitigate metabolic alterations associated with MASLD. Acknowledgment: FAPESP (2022/16108-4)