The Role of Macronutrient Composition in Semipurified Diets in Shaping Distinct Obesity Phenotypes: Evidence for Hepatic Oxidative Stress Involvement

Abstract

While obesity is widely recognized as a global epidemic, the specific roles of food processing and macronutrient composition in driving metabolic dysfunction remain complex. Current animal models often rely on purified diets that may lack translational relevance to human dietary patterns. This study aimed to investigate how the macronutrient imbalances in purified diets influence obesity, metabolic comorbidities, and oxidative stress in adult rats. We compared a commercial grain base diet (C/GB) with two semi-purified diets (SD): a balanced SPD (B/SP) and a high-fat/high-sugar SPD (HFS/SP). The study evaluated body weight trajectories, adiposity distribution, glucose/lipid metabolism, and systemic and tissue-specific oxidative stress in male Wistar rats over a 10-week period. The HFS/SP group exhibited a unique biphasic weight trajectory, characterized by an initial rapid increase in body weight and hyperphagia during the first three weeks, followed by loss and stabilization. This was accompanied by significant dyslipidemia, impaired glucose regulation, hepatic steatosis, and elevated systemic oxidative stress. In contrast, the B/SP group showed continuous weight gain and increased adiposity with redistribution of adipose tissue toward subcutaneous depots, preserved glucose handling, and enhanced fat mobilization. Notably, significantly elevated reactive oxygen species production was localized primarily in the liver of the HFS/SP group. Our findings suggest that the nutritional imbalance in processed foods acts as a critical driver of metabolic disease. Rather than being driven solely by adiposity or calories, metabolic dysfunction is heavily influenced by dietary quality, where high-processing and imbalanced macronutrient intake trigger a rapid transition from compensatory weight gain to pathologically dysregulated metabolic syndrome, which is closely associated with hepatic oxidative stress.