| Summary: | Abstract Fructose consumption has been linked to obesity and increased hepatic de novo lipogenesis (DNL). Excessive caloric intake often confounds the results of fructose studies, and experimental diets are generally low‐fat diets, not representative for westernized diets. Here, we compared the effects of dietary fructose with those of dietary glucose, in adult male and female mice on a starch‐containing moderate high–fat (HF) diet. After 5 weeks fattening on a HF high‐glucose (HF‐G) diet, mice were stratified per sex and assigned to one of the three intervention diets for 6 weeks: HF high fructose (HF‐F), HF with equimolar glucose and fructose (HF‐GF), or HF‐G. Bodyweight (BW) and food intake were measured weekly. Indirect calorimetry was performed on week 5; animals were sacrificed in food‐deprived state on week 6. Data were analyzed within sex. BW gain was similar among animals on the HF‐G, HF‐GF, and HF‐F diets. Cumulative food intake was slightly lower in HF‐F animals (both sexes). However, energy expenditure was not affected, or were circulating insulin and glucose concentrations, and hepatic triglyceride levels at endpoint. Hepatic gene expression analysis showed only minor alterations in hexokinase and glycolysis‐related expression in males, and no alterations in sugar transporters, or DNL‐related enzymes. In females, no consistent alterations in hepatic or small intestine gene expression were seen. Concluding, partial or complete replacement of dietary glucose with fructose does not increase caloric intake, and does not affect BW, hepatic triglyceride levels, or insulin concentrations in male and female mice on a moderate high–fat diet.
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