Effectiveness of dietary modifications in reversing damage induced by high-fat diet in rats

Excessive dietary fat intake is a major health concern, contributing to the increasing prevalence of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD) worldwide; different prevalence between sexes has been postulated but it is not clear. This study evaluated the effects of a high-fat diet (HFD) in Wistar rats and the impact of a transition to standard or antioxidant-rich diets in the same animals, exploring differences between sexes. Female and male animals were maintained for 5 months: control (chow diet) and HFD groups throughout the study, and two intervention groups switched after 3 months from HFD to standard or antioxidant-rich diets. Body weight was monitored, hepatic lipid accumulation, plasma levels of glucose, advanced glycation end-products, interleukin-6, and polyphenolic content, and hepatic oxidative stress markers (catalase, superoxide dismutase, glutathione peroxidase, and malondialdehyde) were measured, along with gene expression related to inflammation and lipid metabolism. HFD significantly increased body weight (females: 123.9 ± 13.57 g; males: 163.1 ± 9.97 g) and hepatic lipid accumulation (female proportion: 9.4 ± 0.4; male proportion: 10.5 ± 0.2) compared with control group (females: 28.96 ± 3.95 g; males: 86.29 ± 3.79 g, p < 0.01; 0% lipid deposits for both sexes), with higher effect on body weight in females. Dietary intervention led to a significant reduction in both parameters and for both sexes. Biomarkers of oxidative stress, inflammation and gene expression analysis showed that dietary modification reversed HFD-induced adverse effects in these parameters, restoring levels comparable to controls; with more consistent effects in animals of both sexes that switched to an antioxidant-rich diet. Indeed, this antioxidant-rich diet group showed higher levels of plasma polyphenols (females: 6.28 ± 0.46 ng/L; males: 6.85 ± 0.49 ng/L, p < 0.001) and a better antioxidant and inflammatory gene expression profile even compared with the group that switched to a chow diet. Overall, dietary modification mitigates several adverse effects of HFD, with antioxidant-rich diets showing greater efficacy across multiple endpoints, with similar effects in both sexes.