Background/Objectives: High sugar intake, particularly fructose, is implicated in obesity and metabolic complications. On the other hand, fructose from fruits and vegetables has undisputed benefits for metabolic health. This raises a paradoxical question-how the same fructose molecule can be associated with detrimental health effects in some studies and beneficial in others. This study investigates how diet and sex interact with fructose to modulate the metabolic outcomes. Methods: Male and female mice were fed different normal chow diets, Boston chow diet (BCD; 23% protein, 22% fat, 55% carbohydrates), Lexington chow diet (LXD; 24% protein, 18% fat, 58% carbohydrates), and low-fat diet (LFD; 20% protein, 10% fat, 70% carbohydrates), supplemented with 30% fructose in water. Results: Fructose-supplemented male mice on BCD gained weight and developed glucose intolerance and hepatic steatosis. Conversely, male mice given fructose on LXD did not gain weight, remained glucose-tolerant, and had normal hepatic lipid content. Furthermore, fructose-fed male mice on LFD did not gain weight. However, upon switching to BCD, they gained weight, exhibited worsening liver steatosis, and advanced hepatic insulin resistance. The effects of fructose are sex-dependent. Thus, female mice did not gain weight and remained insulin-sensitive with fructose supplementation on BCD, despite developing hepatic steatosis. These differences in metabolic outcomes correlate with the propensity of the baseline diet to suppress hepatic ketohexokinase expression and the de novo lipogenesis pathway. This is likely driven by the dietary fat-to-carbohydrate ratio. Conclusions: Metabolic dysfunction attributed to fructose intake is not a universal outcome. Instead, it depends on baseline diet, dietary exposure length, and sex.
Keywords: MASLD; de novo lipogenesis; fructose; insulin resistance; ketohexokinase; metabolic syndrome; sex differences.