Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat

Abstract

Context: Consumption of high-fructose diets promotes hepatic fatty acid synthesis (de novo lipogenesis [DNL]) and an atherogenic lipid profile. It is unclear whether these effects occur independent of positive energy balance and weight gain.

Objectives: We compared the effects of a high-fructose, (25% of energy content) weight-maintaining diet to those of an isocaloric diet with the same macronutrient distribution but in which complex carbohydrate (CCHO) was substituted for fructose.

Design, setting, and participants: Eight healthy men were studied as inpatients for consecutive 9-day periods. Stable isotope tracers were used to measure fractional hepatic DNL and endogenous glucose production (EGP) and its suppression during a euglycemic-hyperinsulinemic clamp. Liver fat was measured by magnetic resonance spectroscopy.

Results: Weight remained stable. Regardless of the order in which the diets were fed, the high-fructose diet was associated with both higher DNL (average, 18.6 ± 1.4% vs 11.0 ± 1.4% for CCHO; P = .001) and higher liver fat (median, +137% of CCHO; P = .016) in all participants. Fasting EGP and insulin-mediated glucose disposal did not differ significantly, but EGP during hyperinsulinemia was greater (0.60 ± 0.07 vs 0.46 ± 0.06 mg/kg/min; P = .013) with the high-fructose diet, suggesting blunted suppression of EGP.

Conclusion: Short-term high-fructose intake was associated with increased DNL and liver fat in healthy men fed weight-maintaining diets.

Figure 1.

Details of study design. A, Overview of the study protocol depicting the timing of the stable isotope infusions, euglycemic-hyperinsulinemic clamp, and magnetic resonance studies. B, Four participants started with the complex carbohydrate diet followed by the high-fructose diet; the other four were fed the diets in the opposite sequence. C, Both diets had identical energy and macronutrient content; the complex carbohydrate diet had a very low fructose content (5% of total energy intake) whereas fructose accounted for half of the total carbohydrate intake on the high-fructose diet (25% of total energy intake).

Figure 2.

Daily weight, obtained after overnight fasting, in the individual participants during the 18-day inpatient study. Open symbols depict weights obtained during complex carbohydrate feeding, filled symbols during high-fructose feeding. Weight remained stable in each participant studied, regardless of the order in which the diets were fed.

Figure 3.

Postprandial fractional DNL, lipid oxidation rates, and triglyceride levels. Data obtained during the high-fructose diet are shown as closed symbols, and those during CCHO feeding as open symbols. A, Postprandial DNL. On day 9 of each dietary period, after fasting overnight, participants began consuming hourly liquid meals at 0600 h. Blood samples were collected periodically throughout the 18-h feeding study. Asterisks denote that DNL during feeding was significantly greater with the high-fructose diet, beginning at 3 h and continuing throughout the tracer/feeding study (P < .05 at each timepoint). B, Integrated AUC for DNL (AUC-DNL). For each participant the AUC-DNL was higher with the high-fructose diet, independent of the order in which the diets were administered. Average AUC-DNL was significantly greater with the fructose diet (P = .002 vs CCHO). C, Lipid oxidation rates. Indirect calorimetry was performed eight times during the feeding study for calculation of lipid oxidation rate. The average rate of lipid oxidation was significantly lower with the high-fructose diet (P = .005 vs CCHO). D, Average postprandial triglyceride levels were significantly higher during high-fructose feeding (P = .002 vs CCHO). Although the magnitude of differences on the two diets varied from participant to participant, in each case the direction of the differences was consistent.

Figure 4.

Liver fat, measured by MRS, was higher with the high-fructose diet than the CCHO diet, regardless of diet order. A, MR spectra from a representative participant after the CCHO diet, then after the high-fructose diet, demonstrating the increase in the lipid peaks with fructose. B, MR spectra from another participant with the opposite diet order. In both cases, the lipid peaks are higher with the fructose diet than with the CCHO diet. All spectra are scaled to the water levels. C, Median values for liver fat were significantly higher with the high-fructose diet when compared with the CCHO diet (P = .016). Error bars show first and third quartiles. All participants showed higher liver fat after the high-fructose diet vs the CCHO diet.