Determining the contribution of a high-fructose corn syrup formulation to hepatic glycogen synthesis during ad-libitum feeding in mice

Excessive sugar intake including high-fructose corn syrup (HFCS) is implicated in the rise of obesity, insulin resistance and non-alcoholic fatty liver disease. Liver glycogen synthesis is influenced by both fructose and insulin signaling. Therefore, the effect of HFCS on hepatic glycogenesis was evaluated in mice feeding ad-libitum. Using deuterated water: the fraction of glycogen derived from triose-P sources, Krebs cycle substrates, and direct pathway+cycling, was measured in 9 normal-chow fed mice (NC) and 12 mice fed normal chow plus a 55% fructose/45% glucose mix in the drinking water at 30% w/v (HFCS-55). This was enriched with [U-C-13]fructose or [U-C-13]glucose to determine the contribution of each to glycogenesis. For NC, direct pathway+cycling, Krebs cycle, and triose-P sources accounted for 66 +/- 0.7%, 23 +/- 0.8% and 11 +/- 0.4% of glycogen synthesis, respectively. HFCS-55 mice had similar direct pathway+cycling (64 +/- 1%) but lower Krebs cycle (12 +/- 1%, p < 0.001) and higher triose-P contributions (24 +/- 1%, p < 0.001). HFCS-55-fructose contributed 17 +/- 1% via triose-P and 2 +/- 0% via Krebs cycle. HFCS-55-glucose contributed 16 +/- 3% via direct pathway and 1 +/- 0% via Krebs cycle. In conclusion, HFCS-55 supplementation resulted in similar hepatic glycogen deposition rates. Indirect pathway contributions shifted from Krebs cycle to Triose-P sources reflecting HFCS-55-fructose utilization, while HFCS-55-glucose was incorporated almost exclusively by the direct pathway.