Sex, diet, and exercise-related differences on metabolic risk factors in C57BL/6J mice consuming diets with and without fructose

High fructose consumption is associated with dysregulated carbohydrate and lipid metabolism. Dysregulated carbohydrate and lipid metabolism often precedes the development of type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Previous research suggests that dietary fructose alters metabolic outcomes in a sex-dependent manner. This study aimed to determine if voluntary wheel running, sex, and dietary fructose interact and impact body weight, liver weight, hepatic fat content, adipocyte morphology, energy expenditure, and normal glucose and lipid metabolism. 17 to 20-week-old male and female C57BL/6J mice (n=64), half of which had access to a running wheel, were fed high-fat diets containing 20% of total energy intake from fructose for 24 weeks. Comprehensive lab animal home cage monitoring systems were used to measure energy expenditure, RER, and lipid and glucose oxidation by indirect calorimetry. Before necropsy, mice received a 1:1 ratio of 0.5 g/kg glucose and fructose to assess postprandial fructose metabolism. When included with a high-fat diet, fructose did not exacerbate outcomes such as weight gain, serum LDL-cholesterol, hepatic steatosis, hepatic collagen deposition, and adipocyte size, and that sex had a greater impact on these outcomes. Previous exposure to fructose from diet significantly raised postprandial blood glucose levels. Sexual dimorphisms were seen in energy expenditure and lipid oxidation levels. Our data suggest that females have an enhanced ability to use dietary fat as fuel and that sex but not access to regular exercise impacts glycemia in mice consuming high levels of energy and fructose.