The propensity of fructose to induce metabolic dysfunction is dependent on the baseline diet, length of the dietary exposure, and sex of the mice.

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Numerous studies have implicated high intake of sugar, particularly fructose, with the development of obesity and metabolic complications. On the other hand, fructose from fruits and vegetables has undisputed benefits for metabolic health. This paradox questions how the same fructose molecule can be associated with detrimental health effects in some studies and beneficial in others. To answer this question, male and female mice were fed different normal chow diets and provided 30% fructose solution in water. Fructose-supplemented male mice on the Boston Chow Diet (BCD=23% protein, 22% fat, 55% carbs) gained weight, developed glucose intolerance and hepatic steatosis. In contrast, male mice on the Lexington Chow Diet (LXD=24% protein, 18% fat, 58% carbs) did not gain weight, remained glucose tolerant, and had normal hepatic lipid content when supplemented with fructose. Furthermore, fructose-fed male mice on a Low-Fat Diet (LFD=20% protein, 10% fat, 70% carbs) didn't gain weight, but once switched to the BCD, they gained weight, exhibited worsening liver steatosis, and more advanced hepatic insulin resistance. The effects of fructose are sex-dependent, as female mice didn't gain weight and remained insulin-sensitive when given fructose on BCD, despite developing hepatic steatosis. The 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. Thus, metabolic dysfunction attributed to fructose intake is not a universal outcome; rather, it depends on the baseline diet, sex, and exposure length.