Cassava-resistant starch type 3 modulates high-fat diet-induced adiposity and transcriptional oxidative stress...

High-fat diets (HFDs) are associated with excessive weight gain and lipid accumulation, contributing to metabolic syndrome. Resistant starch (RS), an indigestible dietary fiber that undergoes colonic fermentation, is proposed to improve metabolic outcomes. This study investigated the effects of cassava-derived resistant starch type 3 (RS3), incorporated into an isocaloric HFD, on body weight, glucose metabolism, lipid deposition, and hepatic redox-related gene expression in healthy rats. Male Wistar rats were fed for 28 days with an isocaloric high-fat diet containing either native cassava starch (HFD-NS) or a diet where a portion of the starch was replaced with RS3 (HFD-RS3). Body weight, food intake, oral glucose tolerance, serum biochemistry, hepatic lipid accumulation, and the expression of sirtuins and antioxidant genes were evaluated. The HFD-RS3 rats exhibited significantly higher food intake than the HFD-NS group; however, total daily calorie intake did not differ significantly between groups. Despite this comparable energy consumption, HFD-RS3 rats exhibited significantly lower body-weight gain, liver weight, visceral fat weight, and reduced hepatic lipid droplets compared to the HFD-NS group. Glucose tolerance showed a modest improvement in the early phase, while fasting glucose, insulin, and lipid profiles remained statistically unchanged. Notably, RS3 supplementation significantly upregulated hepatic Sirt1, catalase (CAT), and TNF-α mRNA expression, while SIRT1 protein concentrations decreased and reactive oxygen species (ROS) concentrations remained stable. These findings suggest that RS3 induces an adaptive transcriptional response to maintain redox and lipid homeostasis without causing functional hepatic injury. Incorporating cassava-derived RS3 into a high-fat diet effectively attenuates weight gain and hepatic lipid accumulation while promoting the transcriptional activation of the antioxidant defense system. These findings highlight RS3 as a potential functional dietary component for supporting metabolic balance under fat-rich nutritional conditions.